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Woods JP, Rackley A, Kwon HR, Olson LE. PDGFRα signaling regulates cartilage and fibrous tissue differentiation during synovial joint development. Nat Commun 2025; 16:4041. [PMID: 40301343 PMCID: PMC12041487 DOI: 10.1038/s41467-025-59207-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 04/14/2025] [Indexed: 05/01/2025] Open
Abstract
Synovial joints develop from mesenchymal structures called interzones, with progenitor cells differentiating into specialized cartilaginous and fibrous tissues of the joint. Platelet-derived growth factor receptor-α (PDGFRα) is a tyrosine kinase expressed by cells of the limb bud, but its role in limb development is unknown. To investigate PDGFRα function, we generated mice expressing mutant PDGFRα with a point mutation (D842V) that increases receptor signaling. Mutant hindlimbs are immobile with knee joints fused by cartilage and lacking ligaments and menisci. The interzone marker Gdf5 is initially expressed at E12.5 but is downregulated thereafter, suggesting a defect in interzone maintenance. Omics analysis of the joint tissues identifies ectopic cartilage matrix expressing genes for cartilage and fibrotic tissue. Thus, elevated PDGFRα signaling corrupts joint development by downregulating Gdf5 and redirecting interzone progenitors into a fibrocartilage fate. This suggests that tight regulation of tyrosine kinase activity is necessary for the development of the mouse knee joint.
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Affiliation(s)
- John P Woods
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Alex Rackley
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Hae Ryong Kwon
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
| | - Lorin E Olson
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
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Hatzikotoulas K, Southam L, Stefansdottir L, Boer CG, McDonald ML, Pett JP, Park YC, Tuerlings M, Mulders R, Barysenka A, Arruda AL, Tragante V, Rocco A, Bittner N, Chen S, Horn S, Srinivasasainagendra V, To K, Katsoula G, Kreitmaier P, Tenghe AMM, Gilly A, Arbeeva L, Chen LG, de Pins AM, Dochtermann D, Henkel C, Höijer J, Ito S, Lind PA, Lukusa-Sawalena B, Minn AKK, Mola-Caminal M, Narita A, Nguyen C, Reimann E, Silberstein MD, Skogholt AH, Tiwari HK, Yau MS, Yue M, Zhao W, Zhou JJ, Alexiadis G, Banasik K, Brunak S, Campbell A, Cheung JTS, Dowsett J, Faquih T, Faul JD, Fei L, Fenstad AM, Funayama T, Gabrielsen ME, Gocho C, Gromov K, Hansen T, Hudjashov G, Ingvarsson T, Johnson JS, Jonsson H, Kakehi S, Karjalainen J, Kasbohm E, Lemmelä S, Lin K, Liu X, Loef M, Mangino M, McCartney D, Millwood IY, Richman J, Roberts MB, Ryan KA, Samartzis D, Shivakumar M, Skou ST, Sugimoto S, Suzuki K, Takuwa H, Teder-Laving M, Thomas L, Tomizuka K, Turman C, Weiss S, Wu TT, Zengini E, Zhang Y, Ferreira MAR, Babis G, Baras A, Barker T, Carey DJ, Cheah KSE, Chen Z, Cheung JPY, Daly M, de Mutsert R, Eaton CB, et alHatzikotoulas K, Southam L, Stefansdottir L, Boer CG, McDonald ML, Pett JP, Park YC, Tuerlings M, Mulders R, Barysenka A, Arruda AL, Tragante V, Rocco A, Bittner N, Chen S, Horn S, Srinivasasainagendra V, To K, Katsoula G, Kreitmaier P, Tenghe AMM, Gilly A, Arbeeva L, Chen LG, de Pins AM, Dochtermann D, Henkel C, Höijer J, Ito S, Lind PA, Lukusa-Sawalena B, Minn AKK, Mola-Caminal M, Narita A, Nguyen C, Reimann E, Silberstein MD, Skogholt AH, Tiwari HK, Yau MS, Yue M, Zhao W, Zhou JJ, Alexiadis G, Banasik K, Brunak S, Campbell A, Cheung JTS, Dowsett J, Faquih T, Faul JD, Fei L, Fenstad AM, Funayama T, Gabrielsen ME, Gocho C, Gromov K, Hansen T, Hudjashov G, Ingvarsson T, Johnson JS, Jonsson H, Kakehi S, Karjalainen J, Kasbohm E, Lemmelä S, Lin K, Liu X, Loef M, Mangino M, McCartney D, Millwood IY, Richman J, Roberts MB, Ryan KA, Samartzis D, Shivakumar M, Skou ST, Sugimoto S, Suzuki K, Takuwa H, Teder-Laving M, Thomas L, Tomizuka K, Turman C, Weiss S, Wu TT, Zengini E, Zhang Y, Ferreira MAR, Babis G, Baras A, Barker T, Carey DJ, Cheah KSE, Chen Z, Cheung JPY, Daly M, de Mutsert R, Eaton CB, Erikstrup C, Furnes ON, Golightly YM, Gudbjartsson DF, Hailer NP, Hayward C, Hochberg MC, Homuth G, Huckins LM, Hveem K, Ikegawa S, Ishijima M, Isomura M, Jones M, Kang JH, Kardia SLR, Kloppenburg M, Kraft P, Kumahashi N, Kuwata S, Lee MTM, Lee PH, Lerner R, Li L, Lietman SA, Lotta L, Lupton MK, Mägi R, Martin NG, McAlindon TE, Medland SE, Michaëlsson K, Mitchell BD, Mook-Kanamori DO, Morris AP, Nabika T, Nagami F, Nelson AE, Ostrowski SR, Palotie A, Pedersen OB, Rosendaal FR, Sakurai-Yageta M, Schmidt CO, Sham PC, Singh JA, Smelser DT, Smith JA, Song YQ, Sørensen E, Tamiya G, Tamura Y, Terao C, Thorleifsson G, Troelsen A, Tsezou A, Uchio Y, Uitterlinden AG, Ullum H, Valdes AM, van Heel DA, Walters RG, Weir DR, Wilkinson JM, Winsvold BS, Yamamoto M, Zwart JA, Stefansson K, Meulenbelt I, Teichmann SA, van Meurs JBJ, Styrkarsdottir U, Zeggini E. Translational genomics of osteoarthritis in 1,962,069 individuals. Nature 2025:10.1038/s41586-025-08771-z. [PMID: 40205036 DOI: 10.1038/s41586-025-08771-z] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 02/11/2025] [Indexed: 04/11/2025]
Abstract
Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes1. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide2. As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFβ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation.
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Affiliation(s)
- Konstantinos Hatzikotoulas
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Lorraine Southam
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | | | - Cindy G Boer
- Department of Internal Medicine, Erasmus MC Medical Center, Rotterdam, The Netherlands
| | - Merry-Lynn McDonald
- Birmingham Veterans Affairs Healthcare System (BVAHS), Birmingham, AL, USA
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
- Department of Epidemiology, School of Public Health, UAB, Birmingham, AL, USA
- Department of Genetics, School of Medicine, UAB, Birmingham, AL, USA
| | - J Patrick Pett
- Wellcome Sanger Institute, Cellular Genetics Programme, Wellcome Genome Campus, Cambridge, UK
| | - Young-Chan Park
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Margo Tuerlings
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Rick Mulders
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Andrei Barysenka
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Ana Luiza Arruda
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | | | - Alison Rocco
- Birmingham Veterans Affairs Healthcare System (BVAHS), Birmingham, AL, USA
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA
| | - Norbert Bittner
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Shibo Chen
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Susanne Horn
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Vinodh Srinivasasainagendra
- Birmingham Veterans Affairs Healthcare System (BVAHS), Birmingham, AL, USA
- Department of Biostatistics, School of Public Health, UAB, Birmingham, AL, USA
| | - Ken To
- Wellcome Sanger Institute, Cellular Genetics Programme, Wellcome Genome Campus, Cambridge, UK
- Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
- Department of Surgery, University of Cambridge, Cambridge, UK
| | - Georgia Katsoula
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Peter Kreitmaier
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Amabel M M Tenghe
- Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tübingen, Germany
| | | | - Liubov Arbeeva
- Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Lane G Chen
- Department of Psychiatry, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | | | - Daniel Dochtermann
- Birmingham Veterans Affairs Healthcare System (BVAHS), Birmingham, AL, USA
| | - Cecilie Henkel
- Clinical Orthopaedic Research Hvidovre (CORH), Department of Orthopaedic Surgery, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Jonas Höijer
- Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Shuji Ito
- Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, Japan
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Penelope A Lind
- Psychiatric Genetics, Brain and Mental Health Research Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
| | | | - Aye Ko Ko Minn
- Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Marina Mola-Caminal
- Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Akira Narita
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Chelsea Nguyen
- Birmingham Veterans Affairs Healthcare System (BVAHS), Birmingham, AL, USA
| | - Ene Reimann
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Micah D Silberstein
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Anne-Heidi Skogholt
- HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Hemant K Tiwari
- Department of Biostatistics, School of Public Health, UAB, Birmingham, AL, USA
| | - Michelle S Yau
- Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA
| | - Ming Yue
- School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Wei Zhao
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Jin J Zhou
- Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - George Alexiadis
- 1st Department of Orthopaedics, KAT General Hospital, Athens, Greece
| | - Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK
| | | | - Joseph Dowsett
- Department of Clinical Immunology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
| | - Tariq Faquih
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Jessica D Faul
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
| | - Lijiang Fei
- Wellcome Sanger Institute, Cellular Genetics Programme, Wellcome Genome Campus, Cambridge, UK
- Cambridge Stem Cell Institute, University of Cambridge, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
| | - Anne Marie Fenstad
- The Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
| | | | - Maiken E Gabrielsen
- HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Chinatsu Gocho
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Kirill Gromov
- Clinical Orthopaedic Research Hvidovre (CORH), Department of Orthopaedic Surgery, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Thomas Hansen
- Danish Headache Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet - Glostrup, Glostrup, Denmark
| | - Georgi Hudjashov
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Thorvaldur Ingvarsson
- Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Jessica S Johnson
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Helgi Jonsson
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
- Department of Medicine, Landspitali The National University Hospital of Iceland, Reykjavik, Iceland
| | - Saori Kakehi
- Department of Metabolism & Endocrinology, Sportology Center, Juntendo University Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Juha Karjalainen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Elisa Kasbohm
- Institute for Community Medicine, SHIP-KEF, University Medicine Greifswald, Greifswald, Germany
| | - Susanna Lemmelä
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- Finnish Institute for Health and Welfare (THL), Helsinki, Finland
| | - Kuang Lin
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Xiaoxi Liu
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Marieke Loef
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Massimo Mangino
- Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK
| | - Daniel McCartney
- Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh, UK
| | - Iona Y Millwood
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Joshua Richman
- Birmingham Veterans Affairs Healthcare System (BVAHS), Birmingham, AL, USA
- Department of Surgery, School of Medicine, UAB, Birmingham, AL, USA
| | - Mary B Roberts
- Center for Primary Care & Prevention, Brown University, Pawtucket, RI, USA
| | - Kathleen A Ryan
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Dino Samartzis
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong SAR, China
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Manu Shivakumar
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Søren T Skou
- Research Unit for Musculoskeletal Function and Physiotherapy, Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
- The Research and Implementation Unit PROgrez, Department of Physiotherapy and Occupational Therapy, Næstved-Slagelse-Ringsted Hospitals, Slagelse, Denmark
| | - Sachiyo Sugimoto
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Ken Suzuki
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hiroshi Takuwa
- Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, Japan
| | - Maris Teder-Laving
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Laurent Thomas
- HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Kohei Tomizuka
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Constance Turman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Stefan Weiss
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Tian T Wu
- Department of Psychiatry, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Eleni Zengini
- 4th Psychiatric Department, Dromokaiteio Psychiatric Hospital, Haidari, Athens, Greece
| | - Yanfei Zhang
- Genomic Medicine Institute, Geisinger Health System, Danville, PA, USA
| | | | - George Babis
- 2nd Department of Orthopaedics, National and Kapodistrian University of Athens, Medical School, 'Konstantopouleio' Hospital, Athens, Greece
| | - Aris Baras
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Tyler Barker
- Sports Medicine Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA
- Intermountain Healthcare, Precision Genomics, Salt Lake City, UT, USA
- Department of Orthopaedics, University of Utah, Salt Lake City, UT, USA
| | - David J Carey
- Department of Genomic Health, Geisinger, Danville, PA, USA
| | - Kathryn S E Cheah
- School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Zhengming Chen
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Jason Pui-Yin Cheung
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong SAR, China
| | - Mark Daly
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Renée de Mutsert
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Charles B Eaton
- Center for Primary Care & Prevention, Brown University, Pawtucket, RI, USA
- Department of Family Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA
- Department of Epidemiology, School of Public Health, Brown University, Providence, RI, USA
| | - Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Ove Nord Furnes
- The Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Yvonne M Golightly
- Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- University of Nebraska Medical Center, Omaha, NE, USA
| | - Daniel F Gudbjartsson
- deCODE Genetics/Amgen, Reykjavik, Iceland
- School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
| | - Nils P Hailer
- Orthopedics, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Caroline Hayward
- MRC Human Genetics Unit IGC, University of Edinburgh, Edinburgh, UK
| | - Marc C Hochberg
- Department of Epidemiology and Public Health, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Georg Homuth
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Laura M Huckins
- Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Kristian Hveem
- HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Levanger, Norway
- Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Shiro Ikegawa
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Muneaki Ishijima
- Department of Medicine for Orthopaedics and Motor Organ, Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Minoru Isomura
- Faculty of Human Sciences, Shimane University, Matsue, Japan
| | | | - Jae H Kang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Sharon L R Kardia
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Margreet Kloppenburg
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Peter Kraft
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Nobuyuki Kumahashi
- Department of Orthopedic Surgery, Matsue Red Cross Hospital, Matsue, Japan
| | - Suguru Kuwata
- Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, Japan
| | | | - Phil H Lee
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Psychiatry, Harvard Medical School, Boston, USA
| | - Robin Lerner
- Blizard Institute, Queen Mary University of London, London, UK
| | - Liming Li
- Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China
| | | | - Luca Lotta
- Regeneron Genetics Center, Tarrytown, NY, USA
| | - Michelle K Lupton
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
- Neurogenetics and Dementia, Brain and Mental Health Research Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Reedik Mägi
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Nicholas G Martin
- Genetic Epidemiology, Brain and Mental Health Research Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Timothy E McAlindon
- Division of Rheumatology, Allergy, & Immunology, Tufts Medical Center, Boston, MA, USA
| | - Sarah E Medland
- Psychiatric Genetics, Brain and Mental Health Research Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- School of Psychology, University of Queensland, Brisbane, Queensland, Australia
- Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Karl Michaëlsson
- Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Braxton D Mitchell
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Andrew P Morris
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK
| | - Toru Nabika
- Department of Functional Pathology, Shimane University School of Medicine, Izumo, Japan
| | - Fuji Nagami
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Amanda E Nelson
- Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sisse Rye Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Aarno Palotie
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Ole Birger Pedersen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Immunology, Zealand University Hospital - Køge, Køge, Denmark
| | - Frits R Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Carsten Oliver Schmidt
- Institute for Community Medicine, SHIP-KEF, University Medicine Greifswald, Greifswald, Germany
| | - Pak Chung Sham
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Jasvinder A Singh
- Birmingham Veterans Affairs Healthcare System (BVAHS), Birmingham, AL, USA
- Department of Epidemiology, School of Public Health, UAB, Birmingham, AL, USA
- Division of Rheumatology and Clinical Immunology, Department of Medicine at the School of Medicine, UAB, Birmingham, AL, USA
- Medicine Service, Michale E. DeBakey VA Medical Center, Houston, TX, USA
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | | | - Jennifer A Smith
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - You-Qiang Song
- School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Erik Sørensen
- Department of Clinical Immunology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
| | - Gen Tamiya
- Tohoku University Graduate School of Medicine, Sendai, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Statistical Genetics Team, Center for Advanced Intelligence Project, RIKEN, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism & Endocrinology, Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
- Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
- The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | | | - Anders Troelsen
- Clinical Academic Group: Research OsteoArthritis Denmark (CAG ROAD), Department of Orthopaedic Surgery, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Aspasia Tsezou
- Laboratory of Cytogenetics and Molecular Genetics, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Yuji Uchio
- Department of Orthopedic Surgery, Shimane University Faculty of Medicine, Izumo, Japan
| | - A G Uitterlinden
- Department of Internal Medicine, Erasmus MC Medical Center, Rotterdam, The Netherlands
| | | | - Ana M Valdes
- Faculty of Medicine & Health Sciences, School of Medicine, University of Nottingham, Nottingham, UK
| | | | - Robin G Walters
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - David R Weir
- Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
| | - J Mark Wilkinson
- School of Medicine and Population Health, The University of Sheffield, Sheffield, UK
| | - Bendik S Winsvold
- HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital and University of Oslo, Oslo, Norway
- Department of Neurology, Oslo University Hospital, Oslo, Norway
| | - Masayuki Yamamoto
- Tohoku University Graduate School of Medicine, Sendai, Japan
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - John-Anker Zwart
- HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital and University of Oslo, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kari Stefansson
- deCODE Genetics/Amgen, Reykjavik, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Ingrid Meulenbelt
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Sarah A Teichmann
- Department of Medicine & Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Joyce B J van Meurs
- Department of Internal Medicine, Erasmus MC Medical Center, Rotterdam, The Netherlands
| | | | - Eleftheria Zeggini
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
- TUM School of Medicine and Health, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany.
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Wang W, Zhuang W, Zeng W, Feng Y, Zhang Z. Review of susceptibility genes in developmental dysplasia of the hip: A comprehensive examination of candidate genes and pathways. Clin Genet 2025; 107:3-12. [PMID: 39307874 DOI: 10.1111/cge.14618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 12/18/2024]
Abstract
Developmental dysplasia of the hip (DDH) is one of the most prevalent skeletal deformities, primarily due to the incompatibility between the acetabulum and femoral head. It includes complete dislocation, partial dislocation, instability with femoral head subluxation, and a range of imaging abnormalities that reflect inadequate acetabular formation. Known risk factors for DDH include positive family history, sex, premature birth, non-cephalic delivery, oligohydramnios, gestational diabetes mellitus, maternal hypertension, associated anomalies, swaddling clothes, intrauterine space restriction, and post-term pregnancy. Various research designs have been employed in DDH studies to identify relevant genes, including candidate gene association studies (CGAS), genome-wide association studies (GWAS), restriction fragment length polymorphism (RFLP), and whole exome sequencing (WES). To date, multiple DDH-associated genes have been identified in various populations. Despite extensive research into the epidemiology, risk factors, and genes associated with DDH, its pathogenesis remains unclear. This study provides a comprehensive summary of DDH research designs and evidence for relevant gene mutations through a PubMed search.
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Affiliation(s)
- Wenla Wang
- Research Institute of Orthopedics, Jiangnan Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
- Hangzhou Xiaoshan Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Wei Zhuang
- Research Institute of Orthopedics, Jiangnan Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
- Hangzhou Xiaoshan Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Wenxiang Zeng
- Research Institute of Orthopedics, Jiangnan Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
- Hangzhou Xiaoshan Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Yuqi Feng
- Research Institute of Orthopedics, Jiangnan Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
- Hangzhou Xiaoshan Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Zhaowei Zhang
- Research Institute of Orthopedics, Jiangnan Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China
- Hangzhou Xiaoshan Hospital of Traditional Chinese Medicine, Hangzhou, China
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Farhud DD, Zarif-Yeganeh M, Arian H, Kashi M, Rezaee T. Clinical Presentation and WES Analysis of a Large Iranian Pedigree in Five Successive Generation Affected to Sever Multiple Synostosis 2 (SYNS2, Farhud Type). IRANIAN JOURNAL OF PUBLIC HEALTH 2024; 53:1381-1393. [PMID: 39430143 PMCID: PMC11488561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 04/11/2024] [Indexed: 10/22/2024]
Abstract
Background Bone Morphogenetic Proteins and the related Growth and Differentiation Factors (GDFs) are much conserved signaling proteins. GDF5 is pivotal for skeletal development. Several skeletal dysplasia and malformation syndromes are known as a result of mutations in GDF5. Multiple Synostosis Syndrome2 (SYNS2) is characterized by tarsal-carpal coalition, humeroradial synostosis, brachydactyly, and proximal symphalangism. In this study, we analyzed a large Iranian pedigree affected with a new type of SYNS2 (Farhud Type) in five successive generations. Methods In this family-based study (1982-2022), Genetic linkage analysis of the pedigree (58affected, 62healthy) excluded the locus on chromosome 17q21-q22 in our previous study. Thus, we focused on 20q11.22 locus and GDF5 gene. Genetic investigations were performed on 16 patients with SYNS2 and 40 healthy individuals. Results Whole-exome-sequencing results identified a heterozygote missense mutation in exon2 of GDF5 (NG_008076.1:g.9239G>A, NM_000557.2:c.1424G>A, S475N, rs121909347). This mutation was found in all patients but not in the unaffected individuals. This missense mutation is notable because S475 is strictly conserved among different species, and it is located in a highly conserved and active mature domain of GDF5 (phyloP100way=7.64). The corresponding defect in GDF5 may have unknown interaction with normal active 3rd and 4th structure of the product. Further bioinformatics study (amino acid multiple alignments) showed that the S475 is a much-conserved residue in many different species. Conclusion These results introduce a new role of GDF5 in pathogenesis of a SYNS2 (Farhud Type), considered in genetic counseling, prenatal diagnosis, and as a potential target for molecular therapy, if possible.
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Affiliation(s)
- Dariush D. Farhud
- School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran
- Research Institute of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Marjan Zarif-Yeganeh
- Research Institute of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
- Dr. Farhud Genetics Clinic, Tehran, Iran
| | - Hajar Arian
- Research Institute of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
- Dr. Farhud Genetics Clinic, Tehran, Iran
| | | | - Tayebeh Rezaee
- Surgical Research Center, Department of Surgery, University of Connecticut Health Center, Farmington, CT, USA
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Leung AOW, Poon ACH, Wang X, Feng C, Chen P, Zheng Z, To MK, Chan WCW, Cheung M, Chan D. Suppression of apoptosis impairs phalangeal joint formation in the pathogenesis of brachydactyly type A1. Nat Commun 2024; 15:2229. [PMID: 38472182 PMCID: PMC10933404 DOI: 10.1038/s41467-024-45053-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 01/12/2024] [Indexed: 03/14/2024] Open
Abstract
Apoptosis occurs during development when a separation of tissues is needed. Synovial joint formation is initiated at the presumptive site (interzone) within a cartilage anlagen, with changes in cellular differentiation leading to cavitation and tissue separation. Apoptosis has been detected in phalangeal joints during development, but its role and regulation have not been defined. Here, we use a mouse model of brachydactyly type A1 (BDA1) with an IhhE95K mutation, to show that a missing middle phalangeal bone is due to the failure of the developing joint to cavitate, associated with reduced apoptosis, and a joint is not formed. We showed an intricate relationship between IHH and interacting partners, CDON and GAS1, in the interzone that regulates apoptosis. We propose a model in which CDON/GAS1 may act as dependence receptors in this context. Normally, the IHH level is low at the center of the interzone, enabling the "ligand-free" CDON/GAS1 to activate cell death for cavitation. In BDA1, a high concentration of IHH suppresses apoptosis. Our findings provided new insights into the role of IHH and CDON in joint formation, with relevance to hedgehog signaling in developmental biology and diseases.
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Affiliation(s)
- Adrian On Wah Leung
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Andrew Chung Hin Poon
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Xue Wang
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chen Feng
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
- Hebei Orthopedic Clinical Research Center, The Third Hospital of Hebei Medical University, 050051, Shijiazhuang, Hebei, China
| | - Peikai Chen
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
- Department of Orthopaedics Surgery and Traumatology, The University of Hong Kong -Shenzhen Hospital (HKU-SZH), Shenzhen, China
| | - Zhengfan Zheng
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Michael KaiTsun To
- Department of Orthopaedics Surgery and Traumatology, The University of Hong Kong -Shenzhen Hospital (HKU-SZH), Shenzhen, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Wilson Cheuk Wing Chan
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China.
- Department of Orthopaedics Surgery and Traumatology, The University of Hong Kong -Shenzhen Hospital (HKU-SZH), Shenzhen, China.
| | - Martin Cheung
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Danny Chan
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China.
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Li J, Liang X, Wang X, Yang P, Jian X, Fu L, Deng A, Liu C, Liu J. A missense GDF5 variant causes brachydactyly type A1 and multiple-synostoses syndrome 2. JOR Spine 2024; 7:e1302. [PMID: 38222807 PMCID: PMC10782059 DOI: 10.1002/jsp2.1302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/16/2023] [Accepted: 11/02/2023] [Indexed: 01/16/2024] Open
Abstract
Objective This study aimed to identify the molecular defects and clinical manifestations in a Chinese family with brachydactyly (BD) type A1 (BDA1) and multiple-synostoses syndrome 2 (SYNS2). Methods A Chinese family with BDA1 and SYNS2 was enrolled in this study. Whole-exome sequencing was used to analyze the gene variants in the proband. The sequences of the candidate pathogenic variant in GDF5 was validated via Sanger sequencing. I-TASSER and PyMOL were used to analyze the functional domains of the corresponding mutant proteins. Results The family was found to have an autosomal-dominantly inherited combination of BDA1 and SYNS2 caused by the S475N variant in the GDF5 gene. The variant was located within the functional region, and the mutated residue was found to be highly conserved among species. Via bioinformatic analyses, we predicted this variant to be deleterious, which perturb the protein function. The substitution of the negatively charged amino acid S475 with the neutral N475 was predicted to disrupt the formation of salt bridges with Y487 and impair the structure, stability, and function of the protein, consequently, the abnormalities in cartilage and bone development ensue. Conclusions A single genetic variant (S475N) which disrupt the formation of salt bridges with Y487, in the interface of the antagonist- and receptor-binding sites of GDF5 concurrently causes two pathological mechanisms. This is the first report of this variant, identified in a Chinese family with BDA1 and SYNS2.
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Affiliation(s)
- Juyi Li
- Department of Pharmacy, The Central Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
| | - Xiaofang Liang
- Department of Dermatology, The Central Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Xiufang Wang
- Department of Pain, The Central Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
| | - Pei Yang
- Department of Radiology, The Central Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
| | - Xiaofei Jian
- Department of Orthopedics, The Central Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
| | - Lei Fu
- Department of Ultrasound, The Central Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
| | - Aiping Deng
- Department of Pharmacy, The Central Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
| | - Chao Liu
- Hubei Key Laboratory of Diabetes and AngiopathyHubei University of Science and TechnologyXianningHubeiChina
| | - Jianxin Liu
- Department of Ultrasound, The Central Hospital of WuhanTongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiChina
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Iacobescu GL, Iacobescu L, Popa MIG, Covache-Busuioc RA, Corlatescu AD, Cirstoiu C. Genomic Determinants of Knee Joint Biomechanics: An Exploration into the Molecular Basis of Locomotor Function, a Narrative Review. Curr Issues Mol Biol 2024; 46:1237-1258. [PMID: 38392197 PMCID: PMC10888373 DOI: 10.3390/cimb46020079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/20/2024] [Accepted: 01/25/2024] [Indexed: 02/24/2024] Open
Abstract
In recent years, the nexus between genetics and biomechanics has garnered significant attention, elucidating the role of genomic determinants in shaping the biomechanical attributes of human joints, specifically the knee. This review seeks to provide a comprehensive exploration of the molecular basis underlying knee joint locomotor function. Leveraging advancements in genomic sequencing, we identified specific genetic markers and polymorphisms tied to key biomechanical features of the knee, such as ligament elasticity, meniscal resilience, and cartilage health. Particular attention was devoted to collagen genes like COL1A1 and COL5A1 and their influence on ligamentous strength and injury susceptibility. We further investigated the genetic underpinnings of knee osteoarthritis onset and progression, as well as the potential for personalized rehabilitation strategies tailored to an individual's genetic profile. We reviewed the impact of genetic factors on knee biomechanics and highlighted the importance of personalized orthopedic interventions. The results hold significant implications for injury prevention, treatment optimization, and the future of regenerative medicine, targeting not only knee joint health but joint health in general.
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Affiliation(s)
- Georgian-Longin Iacobescu
- Orthopaedics and Traumatology Department, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- University Emergency Hospital, 050098 Bucharest, Romania
| | - Loredana Iacobescu
- Orthopaedics and Traumatology Department, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- University Emergency Hospital, 050098 Bucharest, Romania
| | - Mihnea Ioan Gabriel Popa
- Orthopaedics and Traumatology Department, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- University Emergency Hospital, 050098 Bucharest, Romania
| | - Razvan-Adrian Covache-Busuioc
- Orthopaedics and Traumatology Department, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Antonio-Daniel Corlatescu
- Orthopaedics and Traumatology Department, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Catalin Cirstoiu
- Orthopaedics and Traumatology Department, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania
- University Emergency Hospital, 050098 Bucharest, Romania
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Wu M, Wu S, Chen W, Li YP. The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease. Cell Res 2024; 34:101-123. [PMID: 38267638 PMCID: PMC10837209 DOI: 10.1038/s41422-023-00918-9] [Citation(s) in RCA: 98] [Impact Index Per Article: 98.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 12/15/2023] [Indexed: 01/26/2024] Open
Abstract
Transforming growth factor-βs (TGF-βs) and bone morphometric proteins (BMPs) belong to the TGF-β superfamily and perform essential functions during osteoblast and chondrocyte lineage commitment and differentiation, skeletal development, and homeostasis. TGF-βs and BMPs transduce signals through SMAD-dependent and -independent pathways; specifically, they recruit different receptor heterotetramers and R-Smad complexes, resulting in unique biological readouts. BMPs promote osteogenesis, osteoclastogenesis, and chondrogenesis at all differentiation stages, while TGF-βs play different roles in a stage-dependent manner. BMPs and TGF-β have opposite functions in articular cartilage homeostasis. Moreover, TGF-β has a specific role in maintaining the osteocyte network. The precise activation of BMP and TGF-β signaling requires regulatory machinery at multiple levels, including latency control in the matrix, extracellular antagonists, ubiquitination and phosphorylation in the cytoplasm, nucleus-cytoplasm transportation, and transcriptional co-regulation in the nuclei. This review weaves the background information with the latest advances in the signaling facilitated by TGF-βs and BMPs, and the advanced understanding of their diverse physiological functions and regulations. This review also summarizes the human diseases and mouse models associated with disordered TGF-β and BMP signaling. A more precise understanding of the BMP and TGF-β signaling could facilitate the development of bona fide clinical applications in treating bone and cartilage disorders.
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Affiliation(s)
- Mengrui Wu
- Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Shali Wu
- Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Chen
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, USA
| | - Yi-Ping Li
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, USA.
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9
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Grall E, Feregrino C, Fischer S, De Courten A, Sacher F, Hiscock TW, Tschopp P. Self-organized BMP signaling dynamics underlie the development and evolution of digit segmentation patterns in birds and mammals. Proc Natl Acad Sci U S A 2024; 121:e2304470121. [PMID: 38175868 PMCID: PMC10786279 DOI: 10.1073/pnas.2304470121] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 11/03/2023] [Indexed: 01/06/2024] Open
Abstract
Repeating patterns of synovial joints are a highly conserved feature of articulated digits, with variations in joint number and location resulting in diverse digit morphologies and limb functions across the tetrapod clade. During the development of the amniote limb, joints form iteratively within the growing digit ray, as a population of distal progenitors alternately specifies joint and phalanx cell fates to segment the digit into distinct elements. While numerous molecular pathways have been implicated in this fate choice, it remains unclear how they give rise to a repeating pattern. Here, using single-cell RNA sequencing and spatial gene expression profiling, we investigate the transcriptional dynamics of interphalangeal joint specification in vivo. Combined with mathematical modeling, we predict that interactions within the BMP signaling pathway-between the ligand GDF5, the inhibitor NOGGIN, and the intracellular effector pSMAD-result in a self-organizing Turing system that forms periodic joint patterns. Our model is able to recapitulate the spatiotemporal gene expression dynamics observed in vivo, as well as phenocopy digit malformations caused by BMP pathway perturbations. By contrasting in silico simulations with in vivo morphometrics of two morphologically distinct digits, we show how changes in signaling parameters and growth dynamics can result in variations in the size and number of phalanges. Together, our results reveal a self-organizing mechanism that underpins amniote digit segmentation and its evolvability and, more broadly, illustrate how Turing systems based on a single molecular pathway may generate complex repetitive patterns in a wide variety of organisms.
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Affiliation(s)
- Emmanuelle Grall
- Zoology, Department of Environmental Sciences, University of Basel, Basel4051, Switzerland
| | - Christian Feregrino
- Zoology, Department of Environmental Sciences, University of Basel, Basel4051, Switzerland
| | - Sabrina Fischer
- Zoology, Department of Environmental Sciences, University of Basel, Basel4051, Switzerland
| | - Aline De Courten
- Zoology, Department of Environmental Sciences, University of Basel, Basel4051, Switzerland
| | - Fabio Sacher
- Zoology, Department of Environmental Sciences, University of Basel, Basel4051, Switzerland
| | - Tom W. Hiscock
- Institute of Medical Sciences, University of Aberdeen, AberdeenAB25 2ZD, Scotland, United Kingdom
| | - Patrick Tschopp
- Zoology, Department of Environmental Sciences, University of Basel, Basel4051, Switzerland
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10
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Yang Y, Zhu G, Chen F, Zhu Y. Congenital middle radioulnar synostosis: Report of a probable subtype. J Orthop Sci 2023; 28:1189-1192. [PMID: 33906816 DOI: 10.1016/j.jos.2020.12.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/10/2020] [Accepted: 12/16/2020] [Indexed: 10/21/2022]
Affiliation(s)
- Yongjia Yang
- The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, 410007, China.
| | - Guanghui Zhu
- Department of Orthopedics, Hunan Children's Hospital, University of South China, Changsha, 410007, China
| | - Fang Chen
- The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, 410007, China
| | - Yimin Zhu
- The Laboratory of Genetics and Metabolism, Hunan Children's Research Institute (HCRI), Hunan Children's Hospital, University of South China, Changsha, 410007, China; Institute of Emergency Medicine, Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, Hunan Provincial People's Hospital (The First-affiliated Hospital of Hunan Normal University), Changsha, Hunan, China.
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11
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Turgut GT, Kalelioglu IH, Karaman V, Sarac Sivrikoz T, Karaman B, Uyguner ZO, Kalayci T. Fibular Agenesis and Ball-Like Toes Mimicking Preaxial Polydactyly: Prenatal Presentation of Du Pan Syndrome. Mol Syndromol 2023; 14:152-157. [PMID: 37064338 PMCID: PMC10091002 DOI: 10.1159/000527955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 10/25/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction GDF5-BMPR1B signaling pathway-associated chondrodysplasias are a genetically heterogeneous group of conditions with significant phenotypic and genotypic overlap, consisting of Hunter-Thompson-type acromesomelic dysplasia, Grebe dysplasia, and Du Pan syndrome. Constituting a spectrum of clinical severity, these disorders are characterized by disproportionate short stature mainly involving middle and distal segments of the extremities. Du Pan syndrome represents the mildest end of this spectrum with less marked shortened limbs, fibular agenesis or hypoplasia, absence of frequent joint dislocations, and carpotarsal fusions with deformed phalangeal bones. Case Presentation Here, we report the first prenatal diagnosis of Du Pan syndrome based on the sonographic findings of bilateral fibular agenesis and ball-shaped toes mimicking preaxial polydactyly accompanying subtle brachydactyly in the family. GDF5 (NM_000557.5) sequencing identified a homozygous pathogenic variant c.1322T>C, p.(Leu441Pro) in the fetus and confirmed the carrier status in the mother. Discussion We suggest that the presence of bilateral fibular agenesis and the apparent image of preaxial polydactyly of the feet on prenatal ultrasound should alert suspicion to Du Pan syndrome, with the latter possibly being a sonographic pitfall. Alongside the fetal imaging, a detailed clinical examination of the expectant parents is also of great importance in establishing a preliminary diagnosis of Du Pan syndrome, as well as the other GDF5-BMPR1B-associated chondrodysplasias.
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Affiliation(s)
- G. Tutku Turgut
- Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ibrahim Halil Kalelioglu
- Division of Perinatology, Department of Obstetrics and Gynecology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Volkan Karaman
- Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Tugba Sarac Sivrikoz
- Division of Perinatology, Department of Obstetrics and Gynecology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Birsen Karaman
- Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
- Department of Pediatric Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Turkey
| | - Zehra Oya Uyguner
- Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Tugba Kalayci
- Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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12
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Weißenberger M, Wagenbrenner M, Nickel J, Ahlbrecht R, Blunk T, Steinert AF, Gilbert F. Comparative in vitro treatment of mesenchymal stromal cells with GDF-5 and R57A induces chondrogenic differentiation while limiting chondrogenic hypertrophy. J Exp Orthop 2023; 10:29. [PMID: 36943593 PMCID: PMC10030724 DOI: 10.1186/s40634-023-00594-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/08/2023] [Indexed: 03/23/2023] Open
Abstract
PURPOSE Hypertrophic cartilage is an important characteristic of osteoarthritis and can often be found in patients suffering from osteoarthritis. Although the exact pathomechanism remains poorly understood, hypertrophic de-differentiation of chondrocytes also poses a major challenge in the cell-based repair of hyaline cartilage using mesenchymal stromal cells (MSCs). While different members of the transforming growth factor beta (TGF-β) family have been shown to promote chondrogenesis in MSCs, the transition into a hypertrophic phenotype remains a problem. To further examine this topic we compared the effects of the transcription growth and differentiation factor 5 (GDF-5) and the mutant R57A on in vitro chondrogenesis in MSCs. METHODS Bone marrow-derived MSCs (BMSCs) were placed in pellet culture and in-cubated in chondrogenic differentiation medium containing R57A, GDF-5 and TGF-ß1 for 21 days. Chondrogenesis was examined histologically, immunohistochemically, through biochemical assays and by RT-qPCR regarding the expression of chondrogenic marker genes. RESULTS Treatment of BMSCs with R57A led to a dose dependent induction of chondrogenesis in BMSCs. Biochemical assays also showed an elevated glycosaminoglycan (GAG) content and expression of chondrogenic marker genes in corresponding pellets. While treatment with R57A led to superior chondrogenic differentiation compared to treatment with the GDF-5 wild type and similar levels compared to incubation with TGF-ß1, levels of chondrogenic hypertrophy were lower after induction with R57A and the GDF-5 wild type. CONCLUSIONS R57A is a stronger inducer of chondrogenesis in BMSCs than the GDF-5 wild type while leading to lower levels of chondrogenic hypertrophy in comparison with TGF-ß1.
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Affiliation(s)
- Manuel Weißenberger
- Department of Orthopaedic Surgery, Center for Musculoskeletal Research, Julius-Maximilians-University Würzburg, König-Ludwig-Haus, Würzburg, Germany.
- Department of Orthopedic Surgery, University of Wuerzburg, König-Ludwig-Haus, Brettreichstraße 11, 97074, Würzburg, Germany.
| | - Mike Wagenbrenner
- Department of Orthopaedic Surgery, Center for Musculoskeletal Research, Julius-Maximilians-University Würzburg, König-Ludwig-Haus, Würzburg, Germany
- Department of Orthopaedics and Trauma Surgery, Musculoskeletal University Center Munich (MUM), University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Joachim Nickel
- Department of Tissue Engineering and Regenerative Medicine, Julius-Maximilians-University Würzburg, University Hospital, Würzburg, Germany
| | - Rasmus Ahlbrecht
- Department of Orthopaedic Surgery, Center for Musculoskeletal Research, Julius-Maximilians-University Würzburg, König-Ludwig-Haus, Würzburg, Germany
- Department of Trauma-, Hand-, Plastic- and Reconstructive Surgery, Julius-Maximilians-University Würzburg, University Hospital, Würzburg, Germany
| | - Torsten Blunk
- Department of Trauma-, Hand-, Plastic- and Reconstructive Surgery, Julius-Maximilians-University Würzburg, University Hospital, Würzburg, Germany
| | - Andre F Steinert
- Department of Orthopaedic Surgery, Center for Musculoskeletal Research, Julius-Maximilians-University Würzburg, König-Ludwig-Haus, Würzburg, Germany
- Current address:, Department of Orthopaedic, Trauma, Shoulder and Arthroplasty Surgery, Rhön-Klinikum, Campus Bad Neustadt, Bad Neustadt, Germany
| | - Fabian Gilbert
- Department of Orthopaedics and Trauma Surgery, Musculoskeletal University Center Munich (MUM), University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Department of Trauma-, Hand-, Plastic- and Reconstructive Surgery, Julius-Maximilians-University Würzburg, University Hospital, Würzburg, Germany
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13
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Shao J, Liu Y, Zhao S, Sun W, Zhan J, Cao L. A novel variant in the ROR2 gene underlying brachydactyly type B: a case report. BMC Pediatr 2022; 22:528. [PMID: 36064339 PMCID: PMC9446770 DOI: 10.1186/s12887-022-03564-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 08/21/2022] [Indexed: 11/17/2022] Open
Abstract
Background Brachydactyly type B is an autosomal dominant disorder that is characterized by hypoplasia of the distal phalanges and nails and can be divided into brachydactyly type B1 (BDB1) and brachydactyly type B2 (BDB2). BDB1 is the most severe form of brachydactyly and is caused by truncating variants in the receptor tyrosine kinase–like orphan receptor 2 (ROR2) gene. Case presentation Here, we report a five-generation Chinese family with brachydactyly with or without syndactyly. The proband and her mother underwent digital separation in syndactyly, and the genetic analyses of the proband and her parents were provided. The novel heterozygous frameshift variant c.1320dupG, p.(Arg441Alafs*18) in the ROR2 gene was identified in the affected individuals by whole-exome sequencing and Sanger sequencing. The c.1320dupG variant in ROR2 is predicted to produce a truncated protein that lacks tyrosine kinase and serine/threonine- and proline-rich structures and remarkably alters the tertiary structures of the mutant ROR2 protein. Conclusion The c.1320dupG, p.(Arg441Alafs*18) variant in the ROR2 gene has not been reported in any databases thus far and therefore is novel. Our study extends the gene variant spectrum of brachydactyly and may provide information for the genetic counselling of family members. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-022-03564-z.
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Affiliation(s)
- Jiaqi Shao
- College of Kinesiology, Shenyang Sport University, No. 36 Jinqiansong East Road, Sujiatun District, Shenyang, 110102, China
| | - Yue Liu
- Hand SurgeryCentral Hospital Affiliated to Shenyang Medical CollegeTiexi District, Dept.4No. 5 Nanqi West Road, Shenyang, 110024, China
| | - Shuyang Zhao
- College of Kinesiology, Shenyang Sport University, No. 36 Jinqiansong East Road, Sujiatun District, Shenyang, 110102, China
| | - Weisheng Sun
- College of Kinesiology, Shenyang Sport University, No. 36 Jinqiansong East Road, Sujiatun District, Shenyang, 110102, China
| | - Jie Zhan
- Hand SurgeryCentral Hospital Affiliated to Shenyang Medical CollegeTiexi District, Dept.4No. 5 Nanqi West Road, Shenyang, 110024, China.
| | - Lihua Cao
- College of Kinesiology, Shenyang Sport University, No. 36 Jinqiansong East Road, Sujiatun District, Shenyang, 110102, China.
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14
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Li Q, Bai F, Chen S. Frameshift Mutation in a Chinese Patient with Brachydactyly Type C Involving the Third Metacarpal: A Case Report. Orthop Surg 2022; 14:2386-2390. [PMID: 35819086 PMCID: PMC9483038 DOI: 10.1111/os.13383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 05/16/2022] [Accepted: 06/04/2022] [Indexed: 11/26/2022] Open
Abstract
Brachydactyly is a common feature of congenital hand anomalies characterized by shortening of the phalanges and/or metacarpals. Mutation of growth differentiation factor‐5 (GDF5) may result in loss of appearance and function in brachydactyly type C (BDC). Herein, we describe an 11 year‐old Chinese BDC patient with significant shortening of the 1st, 2nd, 3rd, and 5th digits. Notably, according to the analysis of metacarpophalangeal pattern profiles, we do not think the 4th digit appears unaffected as usual. In this patient a novel heterozygous frameshift mutation was identified (c.349delG) causing termination of translation after translating six amino acids from codon 117 (p.A117fs*6). This mutation is located in the propeptide region of GDF5, causing GDF5 haploinsufficiency in BDC. Considering our results expanding the genetic spectrum of BDC‐causing mutations, further molecular analysis to diagnose and reclassify isolated brachydactyly on the basis of genotype rather than phenotype is warranted.
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Affiliation(s)
- Qiuya Li
- Peking University Fourth School of Clinical Medicine, Beijing, China.,Department of Hand Surgery, Beijing Ji Shui Tan Hospital, Beijing, China
| | - Fan Bai
- Peking University Fourth School of Clinical Medicine, Beijing, China.,Department of Hand Surgery, Beijing Ji Shui Tan Hospital, Beijing, China
| | - Shanlin Chen
- Department of Hand Surgery, Beijing Ji Shui Tan Hospital, Beijing, China
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15
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Takahata Y, Hagino H, Kimura A, Urushizaki M, Yamamoto S, Wakamori K, Murakami T, Hata K, Nishimura R. Regulatory Mechanisms of Prg4 and Gdf5 Expression in Articular Cartilage and Functions in Osteoarthritis. Int J Mol Sci 2022; 23:ijms23094672. [PMID: 35563063 PMCID: PMC9105027 DOI: 10.3390/ijms23094672] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/04/2023] Open
Abstract
Owing to the rapid aging of society, the numbers of patients with joint disease continue to increase. Accordingly, a large number of patients require appropriate treatment for osteoarthritis (OA), the most frequent bone and joint disease. Thought to be caused by the degeneration and destruction of articular cartilage following persistent and excessive mechanical stimulation of the joints, OA can significantly impair patient quality of life with symptoms such as knee pain, lower limb muscle weakness, or difficulty walking. Because articular cartilage has a low self-repair ability and an extremely low proliferative capacity, healing of damaged articular cartilage has not been achieved to date. The current pharmaceutical treatment of OA is limited to the slight alleviation of symptoms (e.g., local injection of hyaluronic acid or non-steroidal anti-inflammatory drugs); hence, the development of effective drugs and regenerative therapies for OA is highly desirable. This review article summarizes findings indicating that proteoglycan 4 (Prg4)/lubricin, which is specifically expressed in the superficial zone of articular cartilage and synovium, functions in a protective manner against OA, and covers the transcriptional regulation of Prg4 in articular chondrocytes. We also focused on growth differentiation factor 5 (Gdf5), which is specifically expressed on the surface layer of articular cartilage, particularly in the developmental stage, describing its regulatory mechanisms and functions in joint formation and OA pathogenesis. Because several genetic studies in humans and mice indicate the involvement of these genes in the maintenance of articular cartilage homeostasis and the presentation of OA, molecular targeting of Prg4 and Gdf5 is expected to provide new insights into the aetiology, pathogenesis, and potential treatment of OA.
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16
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Hasenbein I, Sachse A, Hortschansky P, Schmuck KD, Horbert V, Anders C, Lehmann T, Huber R, Maslaris A, Layher F, Braun C, Roth A, Plöger F, Kinne RW. Single Application of Low-Dose, Hydroxyapatite-Bound BMP-2 or GDF-5 Induces Long-Term Bone Formation and Biomechanical Stabilization of a Bone Defect in a Senile Sheep Lumbar Osteopenia Model. Biomedicines 2022; 10:513. [PMID: 35203721 PMCID: PMC8962316 DOI: 10.3390/biomedicines10020513] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 12/13/2022] Open
Abstract
Effects of hydroxyapatite (HA) particles with bone morphogenetic BMP-2 or GDF-5 were compared in sheep lumbar osteopenia; in vitro release in phosphate-buffered saline (PBS) or sheep serum was assessed by ELISA. Lumbar (L) vertebral bone defects (Ø 3.5 mm) were generated in aged, osteopenic female sheep (n = 72; 9.00 ± 0.11 years; mean ± SEM). Treatment was: (a) HA particles (2.5 mg; L5); or (b) particles coated with BMP-2 (1 µg; 10 µg) or GDF-5 (5 µg; 50 µg; L4; all groups n = 6). Untouched vertebrae (L3) served as controls. Three and nine months post-therapy, bone formation was assessed by osteodensitometry, histomorphometry, and biomechanical testing. Cumulative 14-day BMP release was high in serum (76-100%), but max. 1.4% in PBS. In vivo induction of bone formation by HA particles with either growth factor was shown by: (i) significantly increased bone volume, trabecular and cortical thickness (overall increase HA + BMP vs. control close to the injection channel 71%, 110%, and 37%, respectively); (ii) partial significant effects for bone mineral density, bone formation, and compressive strength (increase 17%; 9 months; GDF-5). Treatment effects were not dose-dependent. Combined HA and BMPs (single low-dose) highly augment long-term bone formation and biomechanical stabilization in sheep lumbar osteopenia. Thus, carrier-bound BMP doses 20,000-fold to 1000-fold lower than previously applied appear suitable for spinal fusion/bone regeneration and improved treatment safety.
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Affiliation(s)
- Ines Hasenbein
- Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany; (I.H.); (A.S.); (V.H.); (A.M.); (F.L.)
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany;
| | - André Sachse
- Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany; (I.H.); (A.S.); (V.H.); (A.M.); (F.L.)
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany;
| | - Peter Hortschansky
- Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), 07745 Jena, Germany;
| | - Klaus D. Schmuck
- Johnson & Johnson Medical GmbH, DePuySynthes, 22851 Norderstedt, Germany;
| | - Victoria Horbert
- Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany; (I.H.); (A.S.); (V.H.); (A.M.); (F.L.)
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany;
| | - Christoph Anders
- Division of Motor Research, Pathophysiology and Biomechanics, Experimental Trauma Surgery, Department for Hand, Reconstructive, and Trauma Surgery, Jena University Hospital, 07743 Jena, Germany;
| | - Thomas Lehmann
- Institute of Medical Statistics, Computer Sciences and Data Sciences, Jena University Hospital, 07743 Jena, Germany;
| | - René Huber
- Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany;
| | - Alexander Maslaris
- Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany; (I.H.); (A.S.); (V.H.); (A.M.); (F.L.)
| | - Frank Layher
- Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany; (I.H.); (A.S.); (V.H.); (A.M.); (F.L.)
| | - Christina Braun
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany;
| | - Andreas Roth
- Bereich Endoprothetik/Orthopädie, Klinik für Orthopädie, Unfallchirurgie und Plastische Chirurgie, Uniklinik Leipzig AöR, 04103 Leipzig, Germany;
| | - Frank Plöger
- BIOPHARM GmbH, Czernyring 22, 69115 Heidelberg, Germany;
| | - Raimund W. Kinne
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkliniken Eisenberg GmbH, 07607 Eisenberg, Germany;
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17
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Rolfe RA, Shea CA, Murphy P. Geometric analysis of chondrogenic self-organisation of embryonic limb bud cells in micromass culture. Cell Tissue Res 2022; 388:49-62. [PMID: 34988666 DOI: 10.1007/s00441-021-03564-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 11/19/2021] [Indexed: 11/24/2022]
Abstract
Spatial and temporal control of chondrogenesis generates precise, species-specific patterns of skeletal structures in the developing vertebrate limb. The pattern-template is laid down when mesenchymal cells at the core of the early limb bud condense and undergo chondrogenic differentiation. Although the mechanisms involved in organising such complex patterns are not fully understood, the interplay between BMP and Wnt signalling pathways is fundamental. Primary embryonic limb bud cells grown under high-density micromass culture conditions spontaneously create a simple cartilage nodule pattern, presenting a model to investigate pattern generation. We describe a novel analytical approach to quantify geometric properties and spatial relationships between chondrogenic condensations, utilizing the micromass model. We follow the emergence of pattern in live cultures with nodules forming at regular distances, growing and changing shape over time. Gene expression profiling supports rapid chondrogenesis and transition to hypertrophy, mimicking the process of endochondral ossification within the limb bud. Manipulating the signalling environment through addition of BMP or Wnt ligands, as well as the BMP pathway antagonist Noggin, altered the differentiation profile and nodule pattern. BMP2 addition increased chondrogenesis while WNT3A or Noggin had the opposite effect, but with distinct pattern outcomes. Titrating these pro- and anti-chondrogenic factors and examining the resulting patterns support the hypothesis that regularly spaced cartilage nodules formed by primary limb bud cells in micromass culture are influenced by the balance of Wnt and BMP signalling under a Turing-like mechanism. This study demonstrates an approach for investigating the mechanisms governing chondrogenic spatial organization using simple micromass culture.
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Affiliation(s)
- Rebecca A Rolfe
- Department of Zoology, School of Natural Sciences, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Claire A Shea
- Department of Zoology, School of Natural Sciences, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Paula Murphy
- Department of Zoology, School of Natural Sciences, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.
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18
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Towler OW, Shore EM. BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP). Dev Dyn 2022; 251:164-177. [PMID: 34133058 PMCID: PMC9068236 DOI: 10.1002/dvdy.387] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/07/2021] [Accepted: 05/20/2021] [Indexed: 01/03/2023] Open
Abstract
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disease caused by increased BMP pathway signaling due to mutation of ACVR1, a bone morphogenetic protein (BMP) type 1 receptor. The primary clinical manifestation of FOP is extra-skeletal bone formation (heterotopic ossification) within soft connective tissues. However, the underlying ACVR1 mutation additionally alters skeletal bone development and nearly all people born with FOP have bilateral malformation of the great toes as well as other skeletal malformations at diverse anatomic sites. The specific mechanisms through which ACVR1 mutations and altered BMP pathway signaling in FOP influence skeletal bone formation during development remain to be elucidated; however, recent investigations are providing a clearer understanding of the molecular and developmental processes associated with ACVR1-regulated skeletal formation.
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Affiliation(s)
- Oscar Will Towler
- The Center for Research in FOP & Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA,Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Eileen M. Shore
- The Center for Research in FOP & Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA,Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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19
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Muthuirulan P, Zhao D, Young M, Richard D, Liu Z, Emami A, Portilla G, Hosseinzadeh S, Cao J, Maridas D, Sedlak M, Menghini D, Cheng L, Li L, Ding X, Ding Y, Rosen V, Kiapour AM, Capellini TD. Joint disease-specificity at the regulatory base-pair level. Nat Commun 2021; 12:4161. [PMID: 34230488 PMCID: PMC8260791 DOI: 10.1038/s41467-021-24345-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.
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Affiliation(s)
| | - Dewei Zhao
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Mariel Young
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Daniel Richard
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Zun Liu
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Alireza Emami
- Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Gabriela Portilla
- Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Shayan Hosseinzadeh
- Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jiaxue Cao
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.,Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - David Maridas
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Mary Sedlak
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Danilo Menghini
- Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Liangliang Cheng
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Lu Li
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Xinjia Ding
- Department of Surgery, the Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yan Ding
- Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Vicki Rosen
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Ata M Kiapour
- Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Terence D Capellini
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. .,Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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20
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Genovesi ML, Guadagnolo D, Marchionni E, Giovannetti A, Traversa A, Panzironi N, Bernardo S, Palumbo P, Petrizzelli F, Carella M, Mazza T, Pizzuti A, Caputo V. GDF5 mutation case report and a systematic review of molecular and clinical spectrum: Expanding current knowledge on genotype-phenotype correlations. Bone 2021; 144:115803. [PMID: 33333243 DOI: 10.1016/j.bone.2020.115803] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/09/2020] [Accepted: 12/07/2020] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Brachydactyly is a bone development abnormality presenting with variable phenotypes and different transmission patterns. Mutations in GDF5 (Growth and Differentiation Factor 5, MIM *601146) account for a significant amount of cases. Here, we report on a three-generation family, where the proband and the grandfather have an isolated brachydactyly with features of both type A1 (MIM #112500) and type C (MIM #113100), while the mother shows only subtle hand phenotype signs. MATERIALS AND METHODS Whole Exome Sequencing (WES) was performed on the two affected individuals. An in-depth analysis of GDF5 genotype-phenotype correlations was performed through literature reviewing and retrieving information from several databases to elucidate GDF5-related molecular pathogenic mechanisms. RESULTS WES analysis disclosed a pathogenic variant in GDF5 (NM_000557.5:c.157dup; NP_000548.2:p.Leu53Profs*41; rs778834209), segregating with the phenotype. The frameshift variant was previously associated with Brachydactyly type C (MIM #113100), in heterozygosity, and with the severe Grebe type chondrodysplasia (MIM #200700), in homozygosity. In-depth analysis of literature and databases allowed to retrieve GDF5 mutations and correlations to phenotypes. We disclosed the association of 49 GDF5 pathogenic mutations with eight phenotypes, with both autosomal dominant and recessive transmission patterns. Clinical presentations ranged from severe defects of limb morphogenesis to mild redundant ossification. We suggest that such clinical gradient can be linked to a continuum of GDF5-activity variation, with loss of GDF5 activity underlying bone development defects, and gain of function causing disorders with excessive bone formation. CONCLUSIONS Our analysis of GDF5 pathogenicity mechanisms furtherly supports that mutation and zygosity backgrounds resulting in the same level of GDF5 activity may lead to similar phenotypes. This information can aid in interpreting the potential pathogenic effect of new variants and in supporting an appropriate genetic counseling.
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Affiliation(s)
- Maria Luce Genovesi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Daniele Guadagnolo
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Enrica Marchionni
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Agnese Giovannetti
- Laboratory of Clinical Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Alice Traversa
- Laboratory of Clinical Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Noemi Panzironi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Silvia Bernardo
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Pietro Palumbo
- Laboratory of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Francesco Petrizzelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy; Laboratory of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Massimo Carella
- Laboratory of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Tommaso Mazza
- Laboratory of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Antonio Pizzuti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy; Laboratory of Clinical Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Viviana Caputo
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
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Bednarek M, Trybus M, Kolanowska M, Koziej M, Kiec-Wilk B, Dobosz A, Kotlarek-Łysakowska M, Kubiak-Dydo A, Użarowska-Gąska E, Staręga-Rosłan J, Gaj P, Górzyńska I, Serwan K, Świerniak M, Kot A, Jażdżewski K, Wójcicka A. BMPR1B gene in brachydactyly type 2-A family with de novo R486W mutation and a disease phenotype. Mol Genet Genomic Med 2021; 9:e1594. [PMID: 33486847 PMCID: PMC8104157 DOI: 10.1002/mgg3.1594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/02/2020] [Accepted: 12/15/2020] [Indexed: 12/29/2022] Open
Abstract
Background Brachydactylies are a group of inherited conditions, characterized mainly by the presence of shortened fingers and toes. Based on the patients’ phenotypes, brachydactylies have been subdivided into 10 subtypes. In this study, we have identified a family with two members affected by brachydactyly type A2 (BDA2). BDA2 is caused by mutations in three genes: BMPR1B, BMP2 or GDF5. So far only two studies have reported the BDA2 cases caused by mutations in the BMPR1B gene. Methods We employed next‐generation sequencing to identify mutations in culpable genes. Results and Conclusion In this paper, we report a case of BDA2 resulting from the presence of a heterozygous c.1456C>T, p.Arg486Trp variant in BMPR1B, which was previously associated with BDA2. The next generation sequencing analysis of the patients’ family revealed that the mutation occurred de novo in the proband and was transmitted to his 26‐month‐old son. Although the same variant was confirmed in both patients, their phenotypes were different with more severe manifestation of the disease in the adult.
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Affiliation(s)
- Marcin Bednarek
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland.,University Hospital, Krakow, Poland
| | - Marek Trybus
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland.,University Hospital, Krakow, Poland
| | | | - Mateusz Koziej
- Department of Anatomy, Jagiellonian University Medical College, Kraków, Poland
| | - Beata Kiec-Wilk
- 2nd Department of General Surgery, Jagiellonian University Medical College, Krakow, Poland.,Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Artur Dobosz
- Department of Medical Genetics, Jagiellonian University Medical College, Krakow, Poland
| | | | | | | | | | - Paweł Gaj
- Warsaw Genomics INC., Warszawa, Poland
| | | | | | | | - Adam Kot
- Warsaw Genomics INC., Warszawa, Poland
| | - Krystian Jażdżewski
- Warsaw Genomics INC., Warszawa, Poland.,Laboratory of Human Cancer Genetics, University of Warsaw, Warsaw, Poland
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22
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Gariballa N, Ali BR. Endoplasmic Reticulum Associated Protein Degradation (ERAD) in the Pathology of Diseases Related to TGFβ Signaling Pathway: Future Therapeutic Perspectives. Front Mol Biosci 2020; 7:575608. [PMID: 33195419 PMCID: PMC7658374 DOI: 10.3389/fmolb.2020.575608] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/29/2020] [Indexed: 02/05/2023] Open
Abstract
The transforming growth factor signaling pathway (TGFβ) controls a wide range of cellular activities in adulthood as well as during embryogenesis including cell growth, differentiation, apoptosis, immunological responses and other cellular functions. Therefore, germline mutations in components of the pathway have given rise to a heterogeneous spectrum of hereditary diseases with variable phenotypes associated with malformations in the cardiovascular, muscular and skeletal systems. Our extensive literature and database searches revealed 47 monogenic diseases associated with germline mutations in 24 out of 41 gene variant encoding for TGFβ components. Most of the TGFβ components are membrane or secretory proteins and they are therefore expected to pass through the endoplasmic reticulum (ER), where fidelity of proteins folding is stringently monitored via the ER quality control machineries. Elucidation of the molecular mechanisms of mutant proteins' folding and trafficking showed the implication of ER associated protein degradation (ERAD) in the pathogenesis of some of the diseases. For example, hereditary hemorrhagic telangiectasia types 1 and 2 (HHT1 and HHT2) and familial pulmonary arterial hypertension (FPAH) associated with mutations in Endoglin, ALK1 and BMPR2 components of the signaling pathway, respectively, have all exhibited loss of function phenotype as a result of ER retention of some of their disease-causing variants. In some cases, this has led to premature protein degradation through the proteasomal pathway. We anticipate that ERAD will be involved in the mechanisms of other TGFβ signaling components and therefore warrants further research. In this review, we highlight advances in ER quality control mechanisms and their modulation as a potential therapeutic target in general with particular focus on prospect of their implementation in the treatment of monogenic diseases associated with TGFβ components including HHT1, HHT2, and PAH. In particular, we emphasis the need to establish disease mechanisms and to implement such novel approaches in modulating the molecular pathway of mutant TGFβ components in the quest for restoring protein folding and trafficking as a therapeutic approach.
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Affiliation(s)
- Nesrin Gariballa
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Bassam R. Ali
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Zayed Bin Sultan Center for Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
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23
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Ma SKY, Chan ASF, Rubab A, Chan WCW, Chan D. Extracellular Matrix and Cellular Plasticity in Musculoskeletal Development. Front Cell Dev Biol 2020; 8:781. [PMID: 32984311 PMCID: PMC7477050 DOI: 10.3389/fcell.2020.00781] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
Cellular plasticity refers to the ability of cell fates to be reprogrammed given the proper signals, allowing for dedifferentiation or transdifferentiation into different cell fates. In vitro, this can be induced through direct activation of gene expression, however this process does not naturally occur in vivo. Instead, the microenvironment consisting of the extracellular matrix (ECM) and signaling factors, directs the signals presented to cells. Often the ECM is involved in regulating both biochemical and mechanical signals. In stem cell populations, this niche is necessary for maintenance and proper function of the stem cell pool. However, recent studies have demonstrated that differentiated or lineage restricted cells can exit their current state and transform into another state under different situations during development and regeneration. This may be achieved through (1) cells responding to a changing niche; (2) cells migrating and encountering a new niche; and (3) formation of a transitional niche followed by restoration of the homeostatic niche to sequentially guide cells along the regenerative process. This review focuses on examples in musculoskeletal biology, with the concept of ECM regulating cells and stem cells in development and regeneration, extending beyond the conventional concept of small population of progenitor cells, but under the right circumstances even “lineage-restricted” or differentiated cells can be reprogrammed to enter into a different fate.
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Affiliation(s)
- Sophia Ka Yan Ma
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | | | - Aqsa Rubab
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Wilson Cheuk Wing Chan
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.,Department of Orthopedics Surgery and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,The University of Hong Kong Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China
| | - Danny Chan
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.,The University of Hong Kong Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China
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24
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Zhang M, Lu L, Wei B, Zhang Y, Li X, Shi Y, Ge W, Sun M. Brachydactyly type A3 is caused by a novel 13 bp HOXD13 frameshift deletion in a Chinese family. Am J Med Genet A 2020; 182:2432-2436. [PMID: 32789964 DOI: 10.1002/ajmg.a.61788] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 07/01/2020] [Accepted: 07/11/2020] [Indexed: 12/13/2022]
Abstract
Brachydactyly type A (BDA) is defined as short middle phalanges of the affected digits and is subdivided into four types (BDA1-4). To date, the molecular cause is unknown. However, there is some evidence that pathogenic variants of HOXD13 could be associated with BDA3 and BDA4. Here, we report a Chinese autosomal dominant BDA3 pedigree with a novel HOXD13 mutation. The affected individuals presented with an obviously shorter fifth middle phalanx. The radial side of the middle phalanx was shorter than the ulnar side, and the terminal phalanx of the fifth finger inclined radially and formed classical clinodactyly. Interestingly, the index finger was normal. The initial diagnosis was BDA3. However, the distal third and fourth middle phalanges were also slightly affected, resulting in mild radial clinodactyly. Both feet showed shortening of the middle phalanges, which were fused to the distal phalanges of the second to the fifth toes, as reported in BDA4. Therefore, this pedigree had combined BDA3 and atypical BDA4. By direct sequencing, a 13 bp deletion within exon 1 of HOXD13 (NM_000523.4: c.708_720del13; NP_000514.2: p.Gly237fs) was identified. The 13 bp deletion resulted in a frameshift and premature termination of HOXD13. This study provides further evidences that variants in HOXD13 cause BDA3-BDA4 phenotypes.
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Affiliation(s)
- Mengshu Zhang
- Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Likui Lu
- Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Bin Wei
- Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yingying Zhang
- Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiang Li
- Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yajun Shi
- Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Wei Ge
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Miao Sun
- Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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25
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Andreasson L, Evenbratt H, Simonsson S. GDF5 induces TBX3 in a concentration dependent manner - on a gold nanoparticle gradient. Heliyon 2020; 6:e04133. [PMID: 32551383 PMCID: PMC7292926 DOI: 10.1016/j.heliyon.2020.e04133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 06/03/2019] [Accepted: 06/01/2020] [Indexed: 11/19/2022] Open
Abstract
Organs and tissues, such as cartilage and limbs, are formed during development through an orchestration of growth factors that function as morphogens. Examples of growth factors include growth differentiation factor 5 (GDF5) and transforming growth factors beta 1 and 3 (TGFβ-1 and TGFβ-3) which can specify creation of more than one cell type after forming a concentration gradient in vivo. Here, we studied the impact of morphogen gradients during differentiation of induced pluripotent stem cells (iPSCs) into the chondrocyte lineage. Cell budding zones, consisting of condensed cell aggregates, were observed only in gradients of GDF5. T-box transcription factor 3 (TBX3) was detected specifically in the budding zones (ranging from 500-1,500 particles/μm2) of nuclei and cell vesicles. A homogenous density of GDF5 of 900 particles/μm2 on a surface induced budding and expression of TBX3 after five days in iPSCs. Therefore, we conclude that a gradient of GDF5, as well as the specific homogenous density of GDF5, support the induction of TBX3 in iPCSs. Moreover, differentiation of iPSCs first on GDF5 gradient or homogenous surfaces for five days and then in a three-dimensional structure for five weeks resulted in pellets that expressed TBX3.
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Affiliation(s)
- L. Andreasson
- Cline Scientific AB, Mölndal, SE-431 53, Sweden
- Institute of Biomedicine at Sahlgrenska Academy, Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | | | - S. Simonsson
- Institute of Biomedicine at Sahlgrenska Academy, Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, SE-413 45, Sweden
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26
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Abstract
Bone Morphogenetic Proteins (BMPs) together with the Growth and Differentiation Factors (GDFs) form the largest subgroup of the Transforming Growth Factor (TGF)β family and represent secreted growth factors, which play an essential role in many aspects of cell communication in higher organisms. As morphogens they exert crucial functions during embryonal development, but are also involved in tissue homeostasis and regeneration in the adult organism. Their involvement in maintenance and repair processes of various tissues and organs made these growth factors highly interesting targets for novel pharmaceutical applications in regenerative medicine. A hallmark of the TGFβ protein family is that all of the more than 30 growth factors identified to date signal by binding and hetero-oligomerization of a very limited set of transmembrane serine-threonine kinase receptors, which can be classified into two subgroups termed type I and type II. Only seven type I and five type II receptors exist for all 30plus TGFβ members suggesting a pronounced ligand-receptor promiscuity. Indeed, many TGFβ ligands can bind the same type I or type II receptor and a particular receptor of either subtype can usually interact with and bind various TGFβ ligands. The possible consequence of this ligand-receptor promiscuity is further aggravated by the finding that canonical TGFβ signaling of all family members seemingly results in the activation of just two distinct signaling pathways, that is either SMAD2/3 or SMAD1/5/8 activation. While this would implicate that different ligands can assemble seemingly identical receptor complexes that activate just either one of two distinct pathways, in vitro and in vivo analyses show that the different TGFβ members exert quite distinct biological functions with high specificity. This discrepancy indicates that our current view of TGFβ signaling initiation just by hetero-oligomerization of two receptor subtypes and transduction via two main pathways in an on-off switch manner is too simplified. Hence, the signals generated by the various TGFβ members are either quantitatively interpreted using the subtle differences in their receptor-binding properties leading to ligand-specific modulation of the downstream signaling cascade or additional components participating in the signaling activation complex allow diversification of the encoded signal in a ligand-dependent manner at all cellular levels. In this review we focus on signal specification of TGFβ members, particularly of BMPs and GDFs addressing the role of binding affinities, specificities, and kinetics of individual ligand-receptor interactions for the assembly of specific receptor complexes with potentially distinct signaling properties.
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27
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Ma C, Liu L, Wang FN, Tian HS, Luo Y, Yu R, Fan LL, Li YL. Identification of a novel mutation of NOG in family with proximal symphalangism and early genetic counseling. BMC MEDICAL GENETICS 2019; 20:169. [PMID: 31694554 PMCID: PMC6836329 DOI: 10.1186/s12881-019-0917-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 10/31/2019] [Indexed: 11/10/2022]
Abstract
BACKGROUND Proximal symphalangism is a rare disease with multiple phenotypes including reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger, as well as hearing loss. At present, at least two types of proximal symphalangism have been identified in the clinic. One is proximal symphalangism-1A (SYM1A), which is caused by genetic variants in Noggin (NOG), another is proximal symphalangism-1B (SYM1B), which is resulted from Growth Differentiation Factor 5 (GDF5) mutations. CASE PRESENTATION Here, we reported a Chinese family with symphalangism of the 4th and/or 5th finger and moderate deafness. The proband was a 13-year-old girl with normal intelligence but symphalangism of the 4th finger in the left hand and moderate deafness. Hearing testing and inner ear CT scan suggested that the proband suffered from structural deafness. Family history investigation found that her father (II-3) and grandmother (I-2) also suffered from hearing loss and symphalangism. Target sequencing identified a novel heterozygous NOG mutation, c.690C > G/p.C230W, which was the genetic lesion of the affected family. Bioinformatics analysis and public databases filtering further confirmed the pathogenicity of the novel mutation. Furthermore, we assisted the family to deliver a baby girl who did not carry the mutation by genetic counseling and prenatal diagnosis using amniotic fluid DNA sequencing. CONCLUSION In this study, we identified a novel NOG mutation (c.690C > G/p.C230W) by target sequencing and helped the family to deliver a baby who did not carry the mutation. Our study expanded the spectrum of NOG mutations and contributed to genetic diagnosis and counseling of families with SYM1A.
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Affiliation(s)
- Cong Ma
- Departments of Reproductive Genetics, HeBei General Hospital, ShiJiaZhuang, 050051, China
| | - Lv Liu
- Department of Respiratory Medicine, Diagnosis and Treatment Center of Respiratory Disease, Diagnosis and Treatment Center of Respiratory Disease, the Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Fang-Na Wang
- Departments of Reproductive Genetics, HeBei General Hospital, ShiJiaZhuang, 050051, China
| | - Hai-Shen Tian
- Departments of Reproductive Genetics, HeBei General Hospital, ShiJiaZhuang, 050051, China
| | - Yan Luo
- Departments of Reproductive Genetics, HeBei General Hospital, ShiJiaZhuang, 050051, China
| | - Rong Yu
- Departments of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Liang-Liang Fan
- Department of Cell Biology, The School of Life Sciences, Central South University, Changsha, 410011, Hunan, China.
| | - Ya-Li Li
- Departments of Reproductive Genetics, HeBei General Hospital, ShiJiaZhuang, 050051, China.
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28
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Chijimatsu R, Saito T. Mechanisms of synovial joint and articular cartilage development. Cell Mol Life Sci 2019; 76:3939-3952. [PMID: 31201464 PMCID: PMC11105481 DOI: 10.1007/s00018-019-03191-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/30/2019] [Accepted: 06/11/2019] [Indexed: 12/29/2022]
Abstract
Articular cartilage is formed at the end of epiphyses in the synovial joint cavity and permanently contributes to the smooth movement of synovial joints. Most skeletal elements develop from transient cartilage by a biological process known as endochondral ossification. Accumulating evidence indicates that articular and growth plate cartilage are derived from different cell sources and that different molecules and signaling pathways regulate these two kinds of cartilage. As the first sign of joint development, the interzone emerges at the presumptive joint site within a pre-cartilage tissue. After that, joint cavitation occurs in the center of the interzone, and the cells in the interzone and its surroundings gradually form articular cartilage and the synovial joint. During joint development, the interzone cells continuously migrate out to the epiphyseal cartilage and the surrounding cells influx into the joint region. These complicated phenomena are regulated by various molecules and signaling pathways, including GDF5, Wnt, IHH, PTHrP, BMP, TGF-β, and FGF. Here, we summarize current literature and discuss the molecular mechanisms underlying joint formation and articular development.
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Affiliation(s)
- Ryota Chijimatsu
- Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Taku Saito
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
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29
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Gunnella F, Kunisch E, Horbert V, Maenz S, Bossert J, Jandt KD, Plöger F, Kinne RW. In Vitro Release of Bioactive Bone Morphogenetic Proteins (GDF5, BB-1, and BMP-2) from a PLGA Fiber-Reinforced, Brushite-Forming Calcium Phosphate Cement. Pharmaceutics 2019; 11:pharmaceutics11090455. [PMID: 31484306 PMCID: PMC6781330 DOI: 10.3390/pharmaceutics11090455] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 08/06/2019] [Accepted: 08/23/2019] [Indexed: 12/17/2022] Open
Abstract
Bone regeneration of sheep lumbar osteopenia is promoted by targeted delivery of bone morphogenetic proteins (BMPs) via a biodegradable, brushite-forming calcium-phosphate-cement (CPC) with stabilizing poly(l-lactide-co-glycolide) acid (PLGA) fibers. The present study sought to quantify the release and bioactivity of BMPs from a specific own CPC formulation successfully used in previous in vivo studies. CPC solid bodies with PLGA fibers (0%, 5%, 10%) containing increasing dosages of GDF5, BB-1, and BMP-2 (2 to 1000 µg/mL) were ground and extracted in phosphate-buffered saline (PBS) or pure sheep serum/cell culture medium containing 10% fetal calf serum (FCS; up to 30/31 days). Released BMPs were quantified by ELISA, bioactivity was determined via alkaline phosphatase (ALP) activity after 3-day exposure of different osteogenic cell lines (C2C12; C2C12BRlb with overexpressed BMP-receptor-1b; MCHT-1/26; ATDC-5) and via the influence of the extracts on the expression of osteogenic/chondrogenic genes and proteins in human adipose tissue-derived mesenchymal stem cells (hASCs). There was hardly any BMP release in PBS, whereas in medium + FCS or sheep serum the cumulative release over 30/31 days was 11-34% for GDF5 and 6-17% for BB-1; the release of BMP-2 over 14 days was 25.7%. Addition of 10% PLGA fibers significantly augmented the 14-day release of GDF5 and BMP-2 (to 22.6% and 43.7%, respectively), but not of BB-1 (13.2%). All BMPs proved to be bioactive, as demonstrated by increased ALP activity in several cell lines, with partial enhancement by 10% PLGA fibers, and by a specific, early regulation of osteogenic/chondrogenic genes and proteins in hASCs. Between 10% and 45% of bioactive BMPs were released in vitro from CPC + PLGA fibers over a time period of 14 days, providing a basis for estimating and tailoring therapeutically effective doses for experimental and human in vivo studies.
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Affiliation(s)
- Francesca Gunnella
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany
| | - Elke Kunisch
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany
| | - Victoria Horbert
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany
| | - Stefan Maenz
- Chair of Materials Science, Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, 07743 Jena, Germany
- Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany
| | - Jörg Bossert
- Chair of Materials Science, Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, 07743 Jena, Germany
| | - Klaus D Jandt
- Chair of Materials Science, Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, 07743 Jena, Germany
- Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, 07743 Jena, Germany
- Jena School for Microbial Communication (JSMC), Friedrich Schiller University Jena, 07743 Jena, Germany
| | | | - Raimund W Kinne
- Experimental Rheumatology Unit, Department of Orthopedics, Jena University Hospital, Waldkrankenhaus "Rudolf Elle", Klosterlausnitzer Str. 81, 07607 Eisenberg, Germany.
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30
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Baghdadi T, Nejadhosseinian M, Shirkoohi R, Mostafavi Tabatabaee R, Tamehri SS, Saffari M, Mortazavi SMJ. DNA hypermethylation of GDF5 in developmental dysplasia of the hip (DDH). Mol Genet Genomic Med 2019; 7:e887. [PMID: 31338995 PMCID: PMC6732267 DOI: 10.1002/mgg3.887] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 06/10/2019] [Accepted: 07/05/2019] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION & OBJECTIVE Developmental Dysplasia of the Hip (DDH) is one of the most common congenital skeletal anomalies. Body of evidence suggests that genetic variations in GDF5 are associated with susceptibility to DDH. DDH is a multifactorial disease and its etiology has not been entirely determined. Epigenetic changes such as DNA methylation could be linked to DDH. In this scheme, we hypothesized that changes in GDF5 DNA methylation could predispose a susceptible individual to DDH. METHODS This study consisted of 45 DDH patients and 45 controls with healthy femoral neck cartilage, who underwent hemi-, or total arthroplasty for the femoral neck fracture. A cartilage sample of 1 cm in diameter and 1 mm in the thickness was obtained for DNA extraction. DNA was extracted and DNA methylation of GDF5 was evaluated by metabisulfite method. RESULTS Methylation analysis showed that the promoter of GDF5 in cartilage samples from DDH patients was hypermethylated in comparison to healthy controls (p = .001). CONCLUSION Our study showed that the methylation status of the GDF5 in patients with DDH is dysregulated. This dysregulation indicates that adjustment in the methylation might modify the expression of this gene. Since this gene plays an essential role in cartilage and bone development, thus reducing its expression can contribute to the pathogenesis of DDH. Further studies are needed to elucidate the role of GDF5 in this disease.
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Affiliation(s)
- Taghi Baghdadi
- Department of Orthopedic SurgeryTehran University of Medical SciencesTehranIR Iran
- Joint Reconstruction Research CenterImam Khomeini Hospital, Tehran University of Medical SciencesTehranIR Iran
| | - Mohammad Nejadhosseinian
- Department of Orthopedic SurgeryTehran University of Medical SciencesTehranIR Iran
- Joint Reconstruction Research CenterImam Khomeini Hospital, Tehran University of Medical SciencesTehranIR Iran
| | - Reza Shirkoohi
- Department of Medical GeneticsTehran University of Medical SciencesTehranIR Iran
| | - Reza Mostafavi Tabatabaee
- Joint Reconstruction Research CenterImam Khomeini Hospital, Tehran University of Medical SciencesTehranIR Iran
| | - Seyed S. Tamehri
- Joint Reconstruction Research CenterImam Khomeini Hospital, Tehran University of Medical SciencesTehranIR Iran
- School of medicineTehran University of Medical SciencesTehranIR Iran
| | - Mojtaba Saffari
- Department of medical genetics, School of medicineTehran University of Medical SciencesTehranIR Iran
| | - S. M. Javad Mortazavi
- Department of Orthopedic SurgeryTehran University of Medical SciencesTehranIR Iran
- Joint Reconstruction Research CenterImam Khomeini Hospital, Tehran University of Medical SciencesTehranIR Iran
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Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity. Proc Natl Acad Sci U S A 2019; 116:15505-15513. [PMID: 31315975 DOI: 10.1073/pnas.1906253116] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
TGFβ family ligands, which include the TGFβs, BMPs, and activins, signal by forming a ternary complex with type I and type II receptors. For TGFβs and BMPs, structures of ternary complexes have revealed differences in receptor assembly. However, structural information for how activins assemble a ternary receptor complex is lacking. We report the structure of an activin class member, GDF11, in complex with the type II receptor ActRIIB and the type I receptor Alk5. The structure reveals that receptor positioning is similar to the BMP class, with no interreceptor contacts; however, the type I receptor interactions are shifted toward the ligand fingertips and away from the dimer interface. Mutational analysis shows that ligand type I specificity is derived from differences in the fingertips of the ligands that interact with an extended loop specific to Alk4 and Alk5. The study also reveals differences for how TGFβ and GDF11 bind to the same type I receptor, Alk5. For GDF11, additional contacts at the fingertip region substitute for the interreceptor interactions that are seen for TGFβ, indicating that Alk5 binding to GDF11 is more dependent on direct contacts. In support, we show that a single residue of Alk5 (Phe84), when mutated, abolishes GDF11 signaling, but has little impact on TGFβ signaling. The structure of GDF11/ActRIIB/Alk5 shows that, across the TGFβ family, different mechanisms regulate type I receptor binding and specificity, providing a molecular explanation for how the activin class accommodates low-affinity type I interactions without the requirement of cooperative receptor interactions.
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Hildebrand L, Schmidt-von Kegler M, Walther M, Seemann P, Stange K. Limb specific Acvr1-knockout during embryogenesis in mice exhibits great toe malformation as seen in Fibrodysplasia Ossificans Progressiva (FOP). Dev Dyn 2019; 248:396-403. [PMID: 30854720 PMCID: PMC6593811 DOI: 10.1002/dvdy.24] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 02/25/2019] [Accepted: 03/04/2019] [Indexed: 12/28/2022] Open
Abstract
Purpose This study analyzes Prx1‐specific conditional knockout of Acvr1 aiming to elucidate the endogenous role of Acvr1 during limb formation in early embryonic development. ACVR1 can exhibit activating and inhibiting function in BMP signaling. ACVR1 gain‐of‐function mutations can cause the rare disease fibrodysplasia ossificans progressiva (FOP), where patients develop ectopic bone replacing soft tissue, tendons and ligaments. Methods Whole‐mount in situ hybridization and skeletal preparations revealed that following limb‐specific conditional knockout of Acvr1, metacarpals and proximal phalanges were shortened and additional cartilage and bone elements were formed. Results The analysis of a set of marker genes including ligands and receptors of BMP signaling as well as genes involved in patterning and tendon and cartilage formation, revealed temporal disturbances with distinct spatial patterns. The most striking result was that in the absence of Acvr1 in mesoderm precursor cells, first digits were drastically malformed. Conclusion In FOP, malformation of big toes can serve as a first soft marker in diagnostics. The surprising similarities in phenotype between the described conditional knockout of Acvr1 and the FOP mouse model, indicates a natural inhibitory function of ACVR1. This represents a further step towards better understanding the role of Acvr1 and developing treatment options for FOP.
Limb specific conditional KO of Acvr1 leads to shortened extremities and to heterotopic cartilage and bone formation. Acvr1 is particularly involved in the development of the first digit. Phenotypic similarities between the limb specific cKO of Acvr1 and the FOP mouse model, carrying the gain of function mutation p.R206H in Acvr1, indicates a natural inhibitory function of Acvr1.
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Affiliation(s)
- Laura Hildebrand
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT) / Charité Virchow Campus, Berlin, Germany.,Charité- Universitätsmedizin Berlin, Berlin, Germany.,Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
| | - Mareen Schmidt-von Kegler
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT) / Charité Virchow Campus, Berlin, Germany.,Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - Maria Walther
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT) / Charité Virchow Campus, Berlin, Germany.,Charité- Universitätsmedizin Berlin, Berlin, Germany
| | - Petra Seemann
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT) / Charité Virchow Campus, Berlin, Germany.,Charité- Universitätsmedizin Berlin, Berlin, Germany.,Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
| | - Katja Stange
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT) / Charité Virchow Campus, Berlin, Germany.,Charité- Universitätsmedizin Berlin, Berlin, Germany.,Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
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Rux D, Decker RS, Koyama E, Pacifici M. Joints in the appendicular skeleton: Developmental mechanisms and evolutionary influences. Curr Top Dev Biol 2018; 133:119-151. [PMID: 30902250 PMCID: PMC6988388 DOI: 10.1016/bs.ctdb.2018.11.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The joints are a diverse group of skeletal structures, and their genesis, morphogenesis, and acquisition of specialized tissues have intrigued biologists for decades. Here we review past and recent studies on important aspects of joint development, including the roles of the interzone and morphogenesis of articular cartilage. Studies have documented the requirement of interzone cells in limb joint initiation and formation of most, if not all, joint tissues. We highlight these studies and also report more detailed interzone dissection experiments in chick embryos. Articular cartilage has always received special attention owing to its complex architecture and phenotype and its importance in long-term joint function. We pay particular attention to mechanisms by which neonatal articular cartilage grows and thickens over time and eventually acquires its multi-zone structure and becomes mechanically fit in adults. These and other studies are placed in the context of evolutionary biology, specifically regarding the dramatic changes in limb joint organization during transition from aquatic to land life. We describe previous studies, and include new data, on the knee joints of aquatic axolotls that unlike those in higher vertebrates, are not cavitated, are filled with rigid fibrous tissues and resemble amphiarthroses. We show that when axolotls metamorph to life on land, their intra-knee fibrous tissue becomes sparse and seemingly more flexible and the articular cartilage becomes distinct and acquires a tidemark. In sum, there have been considerable advances toward a better understanding of limb joint development, biological responsiveness, and evolutionary influences, though much remains unclear. Future progress in these fields should also lead to creation of new developmental biology-based tools to repair and regenerate joint tissues in acute and chronic conditions.
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Affiliation(s)
- Danielle Rux
- Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
| | - Rebekah S Decker
- Genomics Institute of the Novartis Research Foundation, San Diego, CA, United States
| | - Eiki Koyama
- Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Maurizio Pacifici
- Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
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34
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Gomez-Puerto MC, Iyengar PV, García de Vinuesa A, Ten Dijke P, Sanchez-Duffhues G. Bone morphogenetic protein receptor signal transduction in human disease. J Pathol 2018; 247:9-20. [PMID: 30246251 PMCID: PMC6587955 DOI: 10.1002/path.5170] [Citation(s) in RCA: 146] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 09/03/2018] [Accepted: 09/13/2018] [Indexed: 12/23/2022]
Abstract
Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physiopathological processes. There are about 15 BMP family members, which signal via three transmembrane type II receptors and four transmembrane type I receptors. Mechanistically, BMP binding leads to phosphorylation of the type I receptor by the type II receptor. This activated heteromeric complex triggers intracellular signaling that is initiated by phosphorylation of receptor‐regulated SMAD1, 5, and 8 (also termed R‐SMADs). Activated R‐SMADs form heteromeric complexes with SMAD4, which engage in specific transcriptional responses. There is convergence along the signaling pathway and, besides the canonical SMAD pathway, BMP‐receptor activation can also induce non‐SMAD signaling. Each step in the pathway is fine‐tuned by positive and negative regulation and crosstalk with other signaling pathways. For example, ligand bioavailability for the receptor can be regulated by ligand‐binding proteins that sequester the ligand from interacting with receptors. Accessory co‐receptors, also known as BMP type III receptors, lack intrinsic enzymatic activity but enhance BMP signaling by presenting ligands to receptors. In this review, we discuss the role of BMP receptor signaling and how corruption of this pathway contributes to cardiovascular and musculoskeletal diseases and cancer. We describe pharmacological tools to interrogate the function of BMP receptor signaling in specific biological processes and focus on how these agents can be used as drugs to inhibit or activate the function of the receptor, thereby normalizing dysregulated BMP signaling. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Maria Catalina Gomez-Puerto
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Prasanna Vasudevan Iyengar
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Amaya García de Vinuesa
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Peter Ten Dijke
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Gonzalo Sanchez-Duffhues
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
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35
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Rafipay A, Berg ALR, Erskine L, Vargesson N. Expression analysis of limb element markers during mouse embryonic development. Dev Dyn 2018; 247:1217-1226. [PMID: 30225906 PMCID: PMC6282987 DOI: 10.1002/dvdy.24671] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 08/13/2018] [Accepted: 08/29/2018] [Indexed: 12/18/2022] Open
Abstract
Background: While data regarding expression of limb element and tissue markers during normal mouse limb development exist, few studies show expression patterns in upper and lower limbs throughout key limb development stages. A comparison to normal developmental events is essential when analyzing development of the limb in mutant mice models. Results: Expression patterns of the joint marker Gdf5, tendon and ligament marker Scleraxis, early muscle marker MyoD1, and blood vessel marker Cadherin5 (Cdh5) are presented during the most active phases of embryonic mouse limb patterning. Anti‐neurofilament staining of developing nerves in the fore‐ and hindlimbs and cartilage formation and progression also are described. Conclusions: This study demonstrates and describes a range of key morphological markers and methods that together can be used to assess normal and abnormal limb development. Developmental Dynamics 247:1217–1226, 2018. © 2018 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists
Expression patterns of molecular markers throughout both fore‐ and hindlimb development ‐ which can be used to assess normal and abnormal development. Detailled description of innervation during fore‐ and hindlimb development confirming innervation first seen after limb patterning events have begun. Description of cartilage development and progression indicates alizarin red staining not seen until E15.5 in both fore‐ and hindlimbs. Hindlimb lags behind forelimb molecularly and morphologically until E14.5. Detailled description of methods used to study fore‐ and hindlimb development.
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Affiliation(s)
- Alexandra Rafipay
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen
| | - Amanda L R Berg
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen
| | - Lynda Erskine
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen
| | - Neil Vargesson
- School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen
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36
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Gamer LW, Pregizer S, Gamer J, Feigenson M, Ionescu A, Li Q, Han L, Rosen V. The Role of Bmp2 in the Maturation and Maintenance of the Murine Knee Joint. J Bone Miner Res 2018; 33:1708-1717. [PMID: 29665134 DOI: 10.1002/jbmr.3441] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 03/28/2018] [Accepted: 04/05/2018] [Indexed: 12/12/2022]
Abstract
Bone morphogenetic proteins (BMPs) are key regulators of skeletal development, growth, and repair. Although BMP signaling is required for synovial joint formation and is also involved in preserving joint function after birth, the role of specific BMP ligands in adult joint homeostasis remains unclear. The purpose of this study was to define the role of Bmp2 in the morphogenesis and maintenance of the knee joint. To do this, we first created Bmp2-LacZ and Gdf5-LacZ knock-in mice and compared their expression patterns in the developing and postnatal murine knee joint. We then generated a knockout mouse model using the Gdf5-cre transgene to specifically delete Bmp2 within synovial joint-forming cells. Joint formation, maturation, and homeostasis were analyzed using histology, immunohistochemistry, qRT-PCR, and atomic force microscopy (AFM)-based nanoindentation to assess the cellular, molecular, and biomechanical changes in meniscus and articular cartilage. Bmp2 is expressed in the articular cartilage and meniscus of the embryonic and adult mouse knee in a pattern distinct from Gdf5. The knee joints of the Bmp2 knockout mice form normally but fail to mature properly. In the absence of Bmp2, the extracellular matrix and shape of the meniscus are altered, resulting in functional deficits in the meniscus and articular cartilage that lead to a progressive osteoarthritis (OA) like knee pathology as the animals age. These findings demonstrate that BMP activity provided by Bmp2 is required for the maturation and maintenance of the murine knee joint and reveal a unique role for Bmp2 that is distinct from Gdf5 in knee joint biology. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Laura W Gamer
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Steven Pregizer
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Jackson Gamer
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Marina Feigenson
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Andreia Ionescu
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Qing Li
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Lin Han
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Vicki Rosen
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
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Andrade AC, Jee YH, Nilsson O. New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth
. Horm Res Paediatr 2018; 88:22-37. [PMID: 28334714 DOI: 10.1159/000455850] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/03/2017] [Indexed: 12/12/2022] Open
Abstract
Idiopathic short stature is a common condition with a heterogeneous etiology. Advances in genetic methods, including genome sequencing techniques and bioinformatics approaches, have emerged as important tools to identify the genetic defects in families with monogenic short stature. These findings have contributed to the understanding of growth regulation and indicate that growth plate chondrogenesis, and therefore linear growth, is governed by a large number of genes important for different signaling pathways and cellular functions, including genetic defects in hormonal regulation, paracrine signaling, cartilage matrix, and fundamental cellular processes. In addition, mutations in the same gene can cause a wide phenotypic spectrum depending on the severity and mode of inheritance of the mutation.
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Affiliation(s)
- Anenisia C Andrade
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Youn Hee Jee
- Section of Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Ola Nilsson
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.,Department of Medical Sciences, Örebro University and University Hospital, Örebro, Sweden
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38
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Sun J, Ermann J, Niu N, Yan G, Yang Y, Shi Y, Zou W. Histone demethylase LSD1 regulates bone mass by controlling WNT7B and BMP2 signaling in osteoblasts. Bone Res 2018; 6:14. [PMID: 29707403 PMCID: PMC5916912 DOI: 10.1038/s41413-018-0015-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 02/03/2018] [Accepted: 03/21/2018] [Indexed: 12/22/2022] Open
Abstract
Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2. LSD1 deficiency resulted in increased BMP2 and WNT7B expression in osteoblasts and enhanced bone formation, while downregulation of WNT7B- and BMP2-related signaling using genetic mouse model or small-molecule inhibitors attenuated bone phenotype in vivo. Furthermore, the LSD1 inhibitor tranylcypromine (TCP) could increase bone mass in mice. These data identify LSD1 as a novel regulator of osteoblast activity and suggest LSD1 inhibition as a potential therapeutic target for treatment of osteoporosis.
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Affiliation(s)
- Jun Sun
- 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Joerg Ermann
- 2Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA
| | - Ningning Niu
- 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Guang Yan
- 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Yang Yang
- 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
| | - Yujiang Shi
- 3Newborn Medicine Division, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, Boston, MA 02115 USA
| | - Weiguo Zou
- 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031 China
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Travieso-Suárez L, Pereda A, Pozo-Román J, Pérez de Nanclares G, Argente J. Braquidactilia tipo C debida a mutación de parada en el gen GDF5. An Pediatr (Barc) 2018; 88:107-109. [DOI: 10.1016/j.anpedi.2017.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 02/27/2017] [Accepted: 03/01/2017] [Indexed: 11/30/2022] Open
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40
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Wang WB, Jia YC, Zhang Z, Xu J, Zuo RT, Kang QL. A novel duplication downstream of BMP2 in a Chinese family with Brachydactyly type A2 (BDA2). Gene 2018; 642:110-115. [DOI: 10.1016/j.gene.2017.11.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 10/16/2017] [Accepted: 11/08/2017] [Indexed: 10/18/2022]
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Travieso-Suárez L, Pereda A, Pozo-Román J, Pérez de Nanclares G, Argente J. Brachydactyly type C due to a nonsense mutation in the GDF5 gene. ANALES DE PEDIATRÍA (ENGLISH EDITION) 2018. [DOI: 10.1016/j.anpede.2017.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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Site-specific chromosomal gene insertion: Flp recombinase versus Cas9 nuclease. Sci Rep 2017; 7:17771. [PMID: 29259215 PMCID: PMC5736728 DOI: 10.1038/s41598-017-17651-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 11/24/2017] [Indexed: 12/16/2022] Open
Abstract
Site-specific recombination systems like those based on the Flp recombinase proved themselves as efficient tools for cell line engineering. The recent emergence of designer nucleases, especially RNA guided endonucleases like Cas9, has considerably broadened the available toolbox for applications like targeted transgene insertions. Here we established a recombinase-mediated cassette exchange (RMCE) protocol for the fast and effective, drug-free isolation of recombinant cells. Distinct fluorescent protein patterns identified the recombination status of individual cells. In derivatives of a CHO master cell line the expression of the introduced transgene of interest could be dramatically increased almost 20-fold by subsequent deletion of the fluorescent protein gene that provided the initial isolation principle. The same master cell line was employed in a comparative analysis using CRISPR/Cas9 for transgene integration in identical loci. Even though the overall targeting efficacy was comparable, multi-loci targeting was considerably more effective for Cas9-mediated transgene insertion when compared to RMCE. While Cas9 is inherently more flexible, our results also alert to the risk of aberrant recombination events around the cut site. Together, this study points at the individual strengths in performance of both systems and provides guidance for their appropriate use.
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43
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Knock-in human GDF5 proregion L373R mutation as a mouse model for proximal symphalangism. Oncotarget 2017; 8:113966-113976. [PMID: 29371961 PMCID: PMC5768378 DOI: 10.18632/oncotarget.23047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 09/20/2017] [Indexed: 01/18/2023] Open
Abstract
Proximal symphalangism (SYM1) is an autosomal dominant disorder, mainly characterized by bony fusions of the proximal phalanges of the hands and feet. GDF5 and NOG were identified to be responsible for SYM1. We have previously reported on a p.Leu373Arg mutation in the GDF5 proregion present in a Chinese family with SYM1. Here, we investigated the effects of the GDF-L373R mutation. The variant caused proteolysis efficiency of GDF5 increased in ATDC5 cells. The variant also caused upregulation of SMAD1/5/8 phosphorylation and increased expression of target genes SMURF1, along with COL2A1 and SOX9 which are factors associated with chondrosis. Furthermore, we developed a human-relevant SYM1 mouse model by making a Gdf5L367R (the orthologous position for L373R in humans) knock-in mouse. Gdf5L367R/+ and Gdf5L367R/L367R mice displayed stiffness and adhesions across the proximal phalanx joint which were in complete accord with SYM1. It was also confirmed the joint formation and development was abnormal in Gdf5L367R/+ and Gdf5L367R/L367R mice, including the failure to develop the primary ossification center and be hypertrophic chondrocytes during embryonic development. This knock-in mouse model offers a tool for assessing the pathogenesis of SYM1 and the function of the GDF5 proregion.
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44
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Tan TY, Gonzaga-Jauregui C, Bhoj EJ, Strauss KA, Brigatti K, Puffenberger E, Li D, Xie L, Das N, Skubas I, Deckelbaum RA, Hughes V, Brydges S, Hatsell S, Siao CJ, Dominguez MG, Economides A, Overton JD, Mayne V, Simm PJ, Jones BO, Eggers S, Le Guyader G, Pelluard F, Haack TB, Sturm M, Riess A, Waldmueller S, Hofbeck M, Steindl K, Joset P, Rauch A, Hakonarson H, Baker NL, Farlie PG. Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions. Am J Hum Genet 2017; 101:985-994. [PMID: 29198724 DOI: 10.1016/j.ajhg.2017.10.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 10/11/2017] [Indexed: 12/25/2022] Open
Abstract
Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.
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Affiliation(s)
- Tiong Yang Tan
- Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia; Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.
| | | | - Elizabeth J Bhoj
- Center for Applied Genomics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4399, USA
| | | | | | | | - Dong Li
- Center for Applied Genomics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4399, USA
| | - LiQin Xie
- Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA
| | - Nanditha Das
- Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA
| | - Ioanna Skubas
- Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA
| | | | | | | | - Sarah Hatsell
- Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA
| | - Chia-Jen Siao
- Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA
| | | | | | - John D Overton
- Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA
| | - Valerie Mayne
- Royal Children's Hospital, Parkville, Melbourne, VIC 3052, Australia
| | - Peter J Simm
- Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Royal Children's Hospital, Parkville, Melbourne, VIC 3052, Australia
| | - Bryn O Jones
- Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Royal Children's Hospital, Parkville, Melbourne, VIC 3052, Australia
| | - Stefanie Eggers
- Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia
| | - Gwenaël Le Guyader
- Department of Medical Genetics, Poitiers University Hospital, Poitiers 86021, France
| | - Fanny Pelluard
- Department of Pathology, Bordeaux University Hospital, Bordeaux 33076, France
| | - Tobias B Haack
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany
| | - Marc Sturm
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany
| | - Angelika Riess
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany
| | - Stephan Waldmueller
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany; Universitätsklinik für Kinder- und Jugendmedizin, Kinderheilkunde II Kardiologie Intensivmedizin Pulmologie, 72076 Tuebingen, Germany
| | - Michael Hofbeck
- Universitätsklinik für Kinder- und Jugendmedizin, Kinderheilkunde II Kardiologie Intensivmedizin Pulmologie, 72076 Tuebingen, Germany
| | - Katharina Steindl
- Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland
| | - Pascal Joset
- Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland
| | - Anita Rauch
- Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland
| | - Hakon Hakonarson
- Center for Applied Genomics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4399, USA
| | - Naomi L Baker
- Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Peter G Farlie
- Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia
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45
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MacFarlane EG, Haupt J, Dietz HC, Shore EM. TGF-β Family Signaling in Connective Tissue and Skeletal Diseases. Cold Spring Harb Perspect Biol 2017; 9:cshperspect.a022269. [PMID: 28246187 DOI: 10.1101/cshperspect.a022269] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The transforming growth factor β (TGF-β) family of signaling molecules, which includes TGF-βs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-β family members play different roles in these tissues, and their activities are often balanced with those of other TGF-β family members and by interactions with other signaling pathways. Perturbations in TGF-β family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-β family of signaling mediators and the extracellular matrix in connective tissues.
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Affiliation(s)
- Elena Gallo MacFarlane
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Julia Haupt
- Department of Orthopedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.,Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Harry C Dietz
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.,Howard Hughes Medical Institute, Bethesda, Maryland 21205
| | - Eileen M Shore
- Department of Orthopedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.,Center for Research in FOP and Related Disorders, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.,Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
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46
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Capellini TD, Chen H, Cao J, Doxey AC, Kiapour AM, Schoor M, Kingsley DM. Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk. Nat Genet 2017; 49:1202-1210. [PMID: 28671685 PMCID: PMC6556117 DOI: 10.1038/ng.3911] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 06/12/2017] [Indexed: 12/19/2022]
Abstract
Variants in GDF5 are associated with human arthritis and decreased height, but the causal mutations are still unknown. We surveyed the Gdf5 locus for regulatory regions in transgenic mice and fine-mapped separate enhancers controlling expression in joints versus growing ends of long bones. A large downstream regulatory region contains a novel growth enhancer (GROW1), which is required for normal Gdf5 expression at ends of developing bones and for normal bone lengths in vivo. Human GROW1 contains a common base-pair change that decreases enhancer activity and colocalizes with peaks of positive selection in humans. The derived allele is rare in Africa but common in Eurasia and is found in Neandertals and Denisovans. Our results suggest that an ancient regulatory variant in GROW1 has been repeatedly selected in northern environments and that past selection on growth phenotypes explains the high frequency of a GDF5 haplotype that also increases arthritis susceptibility in many human populations.
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Affiliation(s)
- Terence D Capellini
- Human Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA.,Department of Developmental Biology, Stanford University, Stanford, California, USA
| | - Hao Chen
- Department of Developmental Biology, Stanford University, Stanford, California, USA
| | - Jiaxue Cao
- Human Evolutionary Biology, Harvard University, Cambridge, Massachusetts, USA
| | - Andrew C Doxey
- Department of Biology, University of Waterloo, Waterloo, Ontario, Canada
| | - Ata M Kiapour
- Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Michael Schoor
- Department of Developmental Biology, Stanford University, Stanford, California, USA
| | - David M Kingsley
- Department of Developmental Biology, Stanford University, Stanford, California, USA.,Howard Hughes Medical Institute, Stanford University, Stanford, California, USA
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47
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Abstract
Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown; but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, and individualized management, and help avoid unnecessary testing for endocrine and other disorders.
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Affiliation(s)
- Youn Hee Jee
- Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive MSC 1103, Bethesda, MD 20892-1103, USA.
| | - Anenisia C Andrade
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solnavägen 1, Solna 171 77, Sweden
| | - Jeffrey Baron
- Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Room 1-3330, 10 Center Drive MSC 1103, Bethesda, MD 20892-1103, USA
| | - Ola Nilsson
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solnavägen 1, Solna 171 77, Sweden; University Hospital, Örebro University, Södra Grev Rosengatan, Örebro 701 85, Sweden
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48
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Ayerst BI, Smith RAA, Nurcombe V, Day AJ, Merry CLR, Cool SM. Growth Differentiation Factor 5-Mediated Enhancement of Chondrocyte Phenotype Is Inhibited by Heparin: Implications for the Use of Heparin in the Clinic and in Tissue Engineering Applications. Tissue Eng Part A 2017; 23:275-292. [PMID: 27899064 PMCID: PMC5397242 DOI: 10.1089/ten.tea.2016.0364] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The highly sulfated glycosaminoglycan (GAG) heparin is widely used in the clinic as an anticoagulant, and researchers are now using it to enhance stem cell expansion/differentiation protocols, as well as to improve the delivery of growth factors for tissue engineering (TE) strategies. Growth differentiation factor 5 (GDF5) belongs to the bone morphogenetic protein family of proteins and is vital for skeletal formation; however, its interaction with heparin and heparan sulfate (HS) has not been studied. We identify GDF5 as a novel heparin/HS binding protein and show that HS proteoglycans are vital in localizing GDF5 to the cell surface. Clinically relevant doses of heparin (≥10 nM), but not equivalent concentrations of HS, were found to inhibit GDF5's biological activity in both human mesenchymal stem/stromal cell-derived chondrocyte pellet cultures and the skeletal cell line ATDC5. We also found that heparin inhibited both GDF5 binding to cell surface HS and GDF5-induced induction of Smad 1/5/8 signaling. Furthermore, GDF5 significantly increased aggrecan gene expression in chondrocyte pellet cultures, without affecting collagen type X expression, making it a promising target for the TE of articular cartilage. Importantly, this study may explain the variable (and disappointing) results seen with heparin-loaded biomaterials for skeletal TE and the adverse skeletal effects reported in the clinic following long-term heparin treatment. Our results caution the use of heparin in the clinic and in TE applications, and prompt the transition to using more specific GAGs (e.g., HS derivatives), with better-defined structures and fewer off-target effects.
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Affiliation(s)
- Bethanie I Ayerst
- 1 Institute of Medical Biology , Agency for Science, Technology and Research (A*STAR), Singapore, Singapore .,2 Wellcome Trust Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biology, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester , Manchester, United Kingdom
| | - Raymond A A Smith
- 1 Institute of Medical Biology , Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Victor Nurcombe
- 1 Institute of Medical Biology , Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Anthony J Day
- 2 Wellcome Trust Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biology, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester , Manchester, United Kingdom
| | - Catherine L R Merry
- 3 School of Materials, University of Manchester , Manchester, United Kingdom .,4 Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, Centre for Biomolecular Sciences, University of Nottingham , Nottingham, United Kingdom
| | - Simon M Cool
- 1 Institute of Medical Biology , Agency for Science, Technology and Research (A*STAR), Singapore, Singapore .,5 Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore
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49
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Salva JE, Merrill AE. Signaling networks in joint development. Dev Dyn 2016; 246:262-274. [PMID: 27859991 DOI: 10.1002/dvdy.24472] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/09/2016] [Accepted: 11/14/2016] [Indexed: 12/21/2022] Open
Abstract
Here we review studies identifying regulatory networks responsible for synovial, cartilaginous, and fibrous joint development. Synovial joints, characterized by the fluid-filled synovial space between the bones, are found in high-mobility regions and are the most common type of joint. Cartilaginous joints such as the intervertebral disc unite adjacent bones through either a hyaline cartilage or a fibrocartilage intermediate. Fibrous joints, which include the cranial sutures, form a direct union between bones through fibrous connective tissue. We describe how the distinct morphologic and histogenic characteristics of these joint classes are established during embryonic development. Collectively, these studies reveal that despite the heterogeneity of joint strength and mobility, joint development throughout the skeleton utilizes common signaling networks via long-range morphogen gradients and direct cell-cell contact. This suggests that different joint types represent specialized variants of homologous developmental modules. Identifying the unifying aspects of the signaling networks between joint classes allows a more complete understanding of the signaling code for joint formation, which is critical to improving strategies for joint regeneration and repair. Developmental Dynamics 246:262-274, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Joanna E Salva
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California
- Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Amy E Merrill
- Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California
- Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California
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50
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Leonidou A, Irving M, Holden S, Katchburian M. Recurrent missense mutation of GDF5 ( p.R438L) causes proximal symphalangism in a British family. World J Orthop 2016; 7:839-842. [PMID: 28032038 PMCID: PMC5155261 DOI: 10.5312/wjo.v7.i12.839] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 08/15/2016] [Accepted: 09/22/2016] [Indexed: 02/06/2023] Open
Abstract
Proximal symphalangism (SYM1B) (OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands, typically of the ring and little finger, with the thumb typically being spared. SYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome, NOG and GDF5. We herein present a British caucasian family with SYM1B caused by a mutation of the GDF5 gene. A mother and her three children presented to the orthopaedic outpatient department predominantly for feet related problems. All patients had multiple tarsal coalitions and hand involvement in the form of either brachydactyly or symphalangism of the proximal and middle phalanx of the little fingers. Genetic testing in the eldest child and his mother identified a heterozygous missense mutation in GDF5 c.1313G>T (p.R438L), thereby establishing SYM1B as the cause of the orthopaedic problems in this family. There were no mutations identified in the NOG gene. This report highlights the importance of thorough history taking, including a three generation family history, and detailed clinical examination of children with fixed planovalgus feet and other family members to detect rare skeletal dysplasia conditions causing pain and deformity, and provides details of the spectrum of problems associated with SYM1B.
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