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Zhu L, Lin W, Kluzek M, Miotla-Zarebska J, Batchelor V, Gardiner M, Chan C, Culmer P, Chanalaris A, Goldberg R, Klein J, Vincent TL. Liposomic lubricants suppress acute inflammatory gene regulation in the joint in vivo. Acta Biomater 2025; 198:366-376. [PMID: 40220945 DOI: 10.1016/j.actbio.2025.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 04/03/2025] [Accepted: 04/09/2025] [Indexed: 04/14/2025]
Abstract
Osteoarthritis (OA) is a widespread, debilitating joint disease associated with articular cartilage degradation. It is driven via mechano-inflammatory pathways, whereby catabolic genes in the cartilage-embedded chondrocytes are presumed up-regulated due to increased shear stress arising from friction at the cartilage surface as joints articulate. The enhanced expression of these cartilage-degrading and inflammatory genes leads to tissue degeneration. However, the nature of the stress, and how the cells within the joint respond to it, are poorly understood. Here we show, in a proof of concept study on a mouse model where surgical joint destabilisation has been carried out to induce OA, that the early up-regulation of the matrix metalloproteinase 3 (Mmp3) gene, a member of the matrix-degrading MMP family, and of the interleukin-1 beta (Il1b) gene, a key mediator of inflammatory response, are significantly suppressed when lipid-based lubricants are injected into the joints. We attribute this to the reduction in frictional stress on the chondrocytes due to the lubricant at the cartilage surface. At the same time, Timp1, a compression but not shear-stress sensitive gene, is unaffected by lubricant. Our results demonstrate that cartilage lubrication modulates catabolic gene regulation in OA, shed strong light on the nature of the chondrocytes' response to shear stress, and have clear implications for novel OA treatments. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) is a widespread, debilitating joint disease associated with degradation of the articular cartilage, the tissue that covers and protects the joint surfaces as they rotate. Such degradation is due to catabolic enzymes expressed by cartilage-embedded chondrocytes (the only cell type in cartilage) in response to mechanical stress. In this proof-of-concept study in a mouse OA model, we show that reduction of cartilage friction by liposome-based lubricants suppresses the production of the catabolic, OA-related genes in chondrocytes. Our findings provide direct evidence in an animal model that catabolic genes are induced in chondrocytes in a mechanosensitive manner, related to the friction at the cartilage surface, and identify putative novel OA treatments through efficient cartilage lubrication.
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Affiliation(s)
- Linyi Zhu
- Kennedy Institute of Rheumatology, Centre for OA Pathogenesis Versus Arthritis, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
| | - Weifeng Lin
- Dept. of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, Israel; Key Laboratory of Bio-Inspired Smart Interfacial Science and Technology of Ministry of Education, School of Chemistry, Beihang University, Beijing 100191
| | - Monika Kluzek
- Dept. of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, Israel; IMol, Polish Academy of Sciences; Warsaw, 02-247, Poland
| | - Jadwiga Miotla-Zarebska
- Kennedy Institute of Rheumatology, Centre for OA Pathogenesis Versus Arthritis, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Vicky Batchelor
- Kennedy Institute of Rheumatology, Centre for OA Pathogenesis Versus Arthritis, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Matthew Gardiner
- Kennedy Institute of Rheumatology, Centre for OA Pathogenesis Versus Arthritis, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Chris Chan
- Kennedy Institute of Rheumatology, Centre for OA Pathogenesis Versus Arthritis, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Peter Culmer
- School of Mechanical Engineering, University of Leeds, UK
| | - Anastasios Chanalaris
- Kennedy Institute of Rheumatology, Centre for OA Pathogenesis Versus Arthritis, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
| | - Ronit Goldberg
- Dept. of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Jacob Klein
- Dept. of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot 7610001, Israel.
| | - Tonia L Vincent
- Kennedy Institute of Rheumatology, Centre for OA Pathogenesis Versus Arthritis, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK
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Dietmar HF, Weidmann PA, Alberton P, Teichwart T, Gerstner M, Renkawitz T, Vortkamp A, Aszodi A, Richter W, Diederichs S. Load activated FGFR and beta1 integrins target distinct chondrocyte mechano-response genes. Matrix Biol 2025:S0945-053X(25)00047-2. [PMID: 40379111 DOI: 10.1016/j.matbio.2025.05.002] [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: 03/18/2025] [Revised: 05/02/2025] [Accepted: 05/12/2025] [Indexed: 05/19/2025]
Abstract
In response to mechanical stimuli, chondrocytes adapt their transcriptional activity, thereby shaping the cellular mechano-response; however, it remains unclear whether the activation of cell surface receptors during mechanical loading converge in the activation of the same mechano-response genes, or whether pathway-specific genes can be defined. We aimed to determine whether load-activated FGF/FGFR signalling and β1 integrins activate ERK and control the same or distinct subsets of mechano-regulated genes. To this end, tissue-engineered neocartilage was generated from murine costal chondrocytes or human articular chondrocytes and subjected to dynamic unconfined compression with or without FGFR inhibition. To assess the role of β1 integrins, neocartilage was generated from embryonic β1 integrin-deficient or wild type costal chondrocytes. Load-activated FGFR signalling drove ERK activation in murine chondrocytes, and partially also in human chondrocytes, and mechano-response genes could be classified according to their regulation: Fosl1, Itga5, Ngf and Timp1 were regulated by load-activated FGFR depending on the developmental stage, whereas β1 integrins controlled Inhba expression. In human chondrocytes, load-activated FGFR signalling controlled expression of BMP2, PTGS2 and DUSP5, but not FOSB. We show here that the chondrocyte loading response is coordinated by concurrent activation of multiple receptors, and identified for the first time distinct target genes of activated receptors. These insights open up the opportunity to pharmacologically shape the mechano-response of chondrocytes in future studies with promising implications for the management of osteoarthritis and the development of novel therapeutic strategies.
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Affiliation(s)
- Helen F Dietmar
- Experimental Orthopaedics, Research Centre for Molecular and Regenerative Orthopaedics, Department of Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
| | - Pia A Weidmann
- Experimental Orthopaedics, Research Centre for Molecular and Regenerative Orthopaedics, Department of Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
| | - Paolo Alberton
- Department of Orthopaedics and Trauma Surgery, Musculoskeletal University Centre Munich (MUM), Ludwig-Maximilians-University (LMU), Munich, Germany; Division of Hand, Plastic, and Aesthetic Surgery, LMU University Hospital, LMU Munich, Germany
| | - Terrilyn Teichwart
- Department of Developmental Biology, Center for Medical Biotechnology, University Duisburg-Essen, Essen, Germany
| | - Matthias Gerstner
- Experimental Orthopaedics, Research Centre for Molecular and Regenerative Orthopaedics, Department of Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
| | - Tobias Renkawitz
- Department of Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
| | - Andrea Vortkamp
- Department of Developmental Biology, Center for Medical Biotechnology, University Duisburg-Essen, Essen, Germany
| | - Attila Aszodi
- Department of Orthopaedics and Trauma Surgery, Musculoskeletal University Centre Munich (MUM), Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Wiltrud Richter
- Experimental Orthopaedics, Research Centre for Molecular and Regenerative Orthopaedics, Department of Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany
| | - Solvig Diederichs
- Experimental Orthopaedics, Research Centre for Molecular and Regenerative Orthopaedics, Department of Orthopaedics, Heidelberg University Hospital, Heidelberg, Germany.
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3
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Zheng C, Wu Y, Luan F, Wei C, Zhang C, Liu W, Wang W, Chen J. Advances in biomimetic hydrogel for articular cartilage defect repair: Enabling immunomodulation and chondrogenesis. Colloids Surf B Biointerfaces 2025; 253:114760. [PMID: 40359898 DOI: 10.1016/j.colsurfb.2025.114760] [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: 02/19/2025] [Revised: 04/22/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025]
Abstract
Articular cartilage defects, as a core pathologic feature in the progression of osteoarthritis, and their irreversible degenerative changes lead to functional impairment and socioeconomic burden for tens of millions of patients worldwide. Hydrogels have become key biomaterials in cartilage regeneration with the three-dimensional network structure, programmable mechanical properties, and cell-adaptive microenvironment of biomimetic extracellular matrix. In recent years, several hydrogel systems with in vitro/in vivo repair potential have been developed by modulating the material topology, dynamic mechanical response, and delivery of bioactive factors, and some of them have entered the clinical translation stage. This review systematically explains the biomimetic design principles of hydrogels. It analyzes the immunomodulation and chondrogenic mechanisms mediated by hydrogels, providing a theoretical framework for the development of next-generation smart cartilage repair materials.
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Affiliation(s)
- Chenxiao Zheng
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China
| | - Yurui Wu
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China
| | - Feifan Luan
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China
| | - Chunwei Wei
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China
| | - Chunye Zhang
- Biomedical and HealthTechnology Innovation Platform, National University of Singapore (Suzhou)Research Institute, Suzhou, Jiangsu 215123, China
| | - Wenjun Liu
- Zhejiang ShangyueBiotechnology Research Center, Hangzhou, Zhejiang 310018, China
| | - Wenjun Wang
- Biomedical and HealthTechnology Innovation Platform, National University of Singapore (Suzhou)Research Institute, Suzhou, Jiangsu 215123, China.
| | - Jiayi Chen
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China.
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Lyu X, Wang J, Su J. Intelligent Manufacturing for Osteoarthritis Organoids. Cell Prolif 2025:e70043. [PMID: 40285592 DOI: 10.1111/cpr.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/22/2025] [Accepted: 04/07/2025] [Indexed: 04/29/2025] Open
Abstract
Osteoarthritis (OA) is the most prevalent degenerative joint disease worldwide, imposing a substantial global disease burden. However, its pathogenesis remains incompletely understood, and effective treatment strategies are still lacking. Organoid technology, in which stem cells or progenitor cells self-organise into miniature tissue structures under three-dimensional (3D) culture conditions, provides a promising in vitro platform for simulating the pathological microenvironment of OA. This approach can be employed to investigate disease mechanisms, carry out high-throughput drug screening and facilitate personalised therapies. This review summarises joint structure, OA pathogenesis and pathological manifestations, thereby establishing the disease context for the application of organoid technology. It then examines the components of the arthrosis organoid system, specifically addressing cartilage, subchondral bone, synovium, skeletal muscle and ligament organoids. Furthermore, it details various strategies for constructing OA organoids, including considerations of cell selection, pathological classification and fabrication techniques. Notably, this review introduces the concept of intelligent manufacturing of OA organoids by incorporating emerging engineering technologies such as artificial intelligence (AI) into the organoid fabrication process, thereby forming an innovative software and hardware cluster. Lastly, this review discusses the challenges currently facing intelligent OA organoid manufacturing and highlights future directions for this rapidly evolving field. By offering a comprehensive overview of state-of-the-art methodologies and challenges, this review anticipates that intelligent, automated fabrication of OA organoids will expedite fundamental research, drug discovery and personalised translational applications in the orthopaedic field.
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Affiliation(s)
- Xukun Lyu
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Clinical Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian Wang
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Translational Medicine, Shanghai University, Shanghai, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, China
| | - Jiacan Su
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Trauma Orthopedics Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Musculoskeletal Injury and Translational Medicine of Organoids, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Translational Medicine, Shanghai University, Shanghai, China
- National Center for Translational Medicine SHU Branch, Shanghai University, Shanghai, China
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5
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Mitsou E, Klein J. Liposome-Based Interventions in Knee Osteoarthritis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2410060. [PMID: 40143645 PMCID: PMC12036560 DOI: 10.1002/smll.202410060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/21/2025] [Indexed: 03/28/2025]
Abstract
Osteoarthritis (OA) is the most common degenerative disease of the joints, causing significant disability and socio-economic burden in the aging population. Simultaneously, however, it is a common occurrence in younger individuals, initiated by joint injuries or obesity alongside other factors. Intravenous and oral pharmaceutical OA management have both been associated with systemic adverse effects, thereby resulting in a growing interest in intra-articular (IA) treatment. IA-administered drugs circumvent the requirement for high dosage, offering immediate access to the site of interest while minimizing any unfavorable effects. Nonetheless, IA-injected drugs, administered in their free form, present low retention time in the knee joint raising the need for multiple injection dosage regimens, while their capability to target the cartilage or specific cell populations is limited. Liposomes, due to their unique characteristics and tunable nature, have proven to be excellent candidates for the management of knee OA. This review explores the last decade's research on the efficacy of various IA liposomal formulations, investigating their multifaceted properties as pharmaceutical carriers, lubricating agents, and a basis for combinatorial approaches paving the way to novel treatment solutions for OA.
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Affiliation(s)
- Evgenia Mitsou
- Department of Molecular Chemistry and Materials ScienceWeizmann Institute of ScienceHertzl Street 234Rehovot7610001Israel
- Present address:
Institute of Chemical BiologyNational Hellenic Research Foundation48, Vassileos Constantinou Ave.Athens11635Greece
| | - Jacob Klein
- Department of Molecular Chemistry and Materials ScienceWeizmann Institute of ScienceHertzl Street 234Rehovot7610001Israel
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Li Z, Li Z, Cheng Q, Nie X, Cui Y, Du B, Ren T, Xu Y, Ma T. α-klotho reduces susceptibility to osteoarthritis: evidence from cross-sectional studies and Mendelian randomization. Front Endocrinol (Lausanne) 2024; 15:1450472. [PMID: 39629050 PMCID: PMC11611571 DOI: 10.3389/fendo.2024.1450472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 10/31/2024] [Indexed: 12/06/2024] Open
Abstract
Background Despite extensive research, the association between serum α-klotho levels and osteoarthritis (OA) remains unclear, predominantly relying on findings from OA mouse models. This study used data from the National Health and Nutrition Examination Survey (NHANES) to conduct a cross-sectional study examining the relationship between α-klotho and human OA. In addition, we used Mendelian randomization (MR) to genetically infer a causal relationship between serum α-klotho and the three OA subtypes. Method A cohort of 12,037 subjects from NHANES (2007-2016) was analyzed. Multivariate logistic regression was utilized to examine the association between α-klotho concentration and OA, alongside subgroup analysis and interaction tests. Additionally, a two-sample bi-directional MR analysis was conducted to evaluate the relationship between serum α-klotho and three OA subtypes, including all OA, hip OA, and knee OA, employing the inverse variance weighting (IVW) method as the primary approach. Results Following adjustment for covariates, a nonlinear negative correlation between serum α-klotho and OA was observed (OR=0.77; 95% CI, 0.68-0.88, p < 0.0001). The IVW method revealed that higher serum α-klotho levels were associated with decreased susceptibility to hip OA (OR = 0.92, 95% CI: 0.87-0.98, P = 9.64×10-3). However, MR analysis did not establish a causal relationship between serum α-klotho and OA or knee OA. Inverse MR also indicated that the three subtypes of OA do not causally affect serum α-klotho concentrations. Conclusions In cross-sectional studies, α-klotho showed a nonlinear negative correlation with OA. MR analysis of outcomes was not identical to cross-sectional studies.
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Affiliation(s)
- Zhao Li
- Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Zhong Li
- Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Qisheng Cheng
- Department of Orthopedic Center, The First Hospital of Jilin University, Changchun, China
| | - Xinlin Nie
- Department of Orthopedic Center, The First Hospital of Jilin University, Changchun, China
| | - Yu Cui
- Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Bing Du
- Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Taotao Ren
- Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Yibo Xu
- Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Teng Ma
- Honghui Hospital, Xi’an Jiaotong University, Xi’an, China
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7
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Lan M, Liu Y, Liu J, Zhang J, Haider MA, Zhang Y, Zhang Q. Matrix Viscoelasticity Tunes the Mechanobiological Behavior of Chondrocytes. Cell Biochem Funct 2024; 42:e4126. [PMID: 39324844 DOI: 10.1002/cbf.4126] [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: 04/18/2024] [Revised: 08/25/2024] [Accepted: 09/10/2024] [Indexed: 09/27/2024]
Abstract
In articular cartilage, the pericellular matrix acting as a specialized mechanical microenvironment modulates environmental signals to chondrocytes through mechanotransduction. Matrix viscoelastic alterations during cartilage development and osteoarthritis (OA) degeneration play an important role in regulating chondrocyte fate and cartilage matrix homeostasis. In recent years, scientists are gradually realizing the importance of matrix viscoelasticity in regulating chondrocyte function and phenotype. Notably, this is an emerging field, and this review summarizes the existing literatures to the best of our knowledge. This review provides an overview of the viscoelastic properties of hydrogels and the role of matrix viscoelasticity in directing chondrocyte behavior. In this review, we elaborated the mechanotransuction mechanisms by which cells sense and respond to the viscoelastic environment and also discussed the underlying signaling pathways. Moreover, emerging insights into the role of matrix viscoelasticity in regulating chondrocyte function and cartilage formation shed light into designing cell-instructive biomaterial. We also describe the potential use of viscoelastic biomaterials in cartilage tissue engineering and regenerative medicine. Future perspectives on mechanobiological comprehension of the viscoelastic behaviors involved in tissue homeostasis, cellular responses, and biomaterial design are highlighted. Finally, this review also highlights recent strategies utilizing viscoelastic hydrogels for designing cartilage-on-a-chip.
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Affiliation(s)
- Minhua Lan
- College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, China
| | - Yanli Liu
- College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, China
| | - Junjiang Liu
- College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, China
| | - Jing Zhang
- College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, China
| | - Muhammad Adnan Haider
- College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, China
| | - Yanjun Zhang
- College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, China
- Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
| | - Quanyou Zhang
- College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, China
- Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
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Li HZ, Zhang JL, Yuan DL, Xie WQ, Ladel CH, Mobasheri A, Li YS. Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family. Mil Med Res 2024; 11:40. [PMID: 38902808 PMCID: PMC11191355 DOI: 10.1186/s40779-024-00544-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 06/12/2024] [Indexed: 06/22/2024] Open
Abstract
Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.
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Affiliation(s)
- Heng-Zhen Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jing-Lve Zhang
- Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
- Xiangya School of Medicine Central, South University, Changsha, 410083, China
| | - Dong-Liang Yuan
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- Xiangya School of Medicine Central, South University, Changsha, 410083, China
| | - Wen-Qing Xie
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | | | - Ali Mobasheri
- Faculty of Medicine, Research Unit of Health Sciences and Technology, University of Oulu, 90014, Oulu, Finland.
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, 08406, Vilnius, Lithuania.
- Department of Rheumatology and Clinical Immunology, Universitair Medisch Centrum Utrecht, Utrecht, 3508, GA, the Netherlands.
- Department of Joint Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
- World Health Organization Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging, Université de Liège, B-4000, Liège, Belgium.
| | - Yu-Sheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Li H, Tang Y, Liu Z, Chen K, Zhang K, Hu S, Pan C, Yang H, Li B, Chen H. Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling. Bone Res 2024; 12:34. [PMID: 38816384 PMCID: PMC11139958 DOI: 10.1038/s41413-024-00331-x] [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: 08/29/2023] [Revised: 02/29/2024] [Accepted: 04/01/2024] [Indexed: 06/01/2024] Open
Abstract
Degenerated endplate appears with cheese-like morphology and sensory innervation, contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.1 However, the origin and development mechanism of the cheese-like morphology remain unclear. Here in this study, we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change. Transcriptome sequencing of the endplate chondrocytes under abnormal stress revealed that the Hippo signaling was key for this process. Activation of Hippo signaling or knockout of the key gene Yap1 in the cartilage endplate severed the cheese-like morphological change and disc degeneration after lumbar spine instability (LSI) surgery, while blocking the Hippo signaling reversed this process. Meanwhile, transcriptome sequencing data also showed osteoclast differentiation related gene set expression was up regulated in the endplate chondrocytes under abnormal mechanical stress, which was activated after the Hippo signaling. Among the discovered osteoclast differentiation gene set, CCL3 was found to be largely released from the chondrocytes under abnormal stress, which functioned to recruit and promote osteoclasts formation for cartilage endplate remodeling. Over-expression of Yap1 inhibited CCL3 transcription by blocking its promoter, which then reversed the endplate from remodeling to the cheese-like morphology. Finally, LSI-induced cartilage endplate remodeling was successfully rescued by local injection of an AAV5 wrapped Yap1 over-expression plasmid at the site. These findings suggest that the Hippo signaling induced osteoclast gene set activation in the cartilage endplate is a potential new target for the management of instability induced low back pain and lumbar degeneration.
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Affiliation(s)
- Hanwen Li
- Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, P.R. China
- Orthopedic Institute, Suzhou Medical College, Soochow University, Suzhou, P.R. China
| | - Yingchuang Tang
- Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, P.R. China
- Orthopedic Institute, Suzhou Medical College, Soochow University, Suzhou, P.R. China
| | - Zixiang Liu
- Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Kangwu Chen
- Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Kai Zhang
- Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, P.R. China
| | - Sihan Hu
- Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, P.R. China
- Orthopedic Institute, Suzhou Medical College, Soochow University, Suzhou, P.R. China
| | - Chun Pan
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, P.R. China
| | - Huilin Yang
- Department of Orthopedic Surgery, First Affiliated Hospital of Soochow University, Suzhou, P.R. China.
- Orthopedic Institute, Suzhou Medical College, Soochow University, Suzhou, P.R. China.
| | - Bin Li
- Orthopedic Institute, Suzhou Medical College, Soochow University, Suzhou, P.R. China.
| | - Hao Chen
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, P.R. China.
- Department of Orthopedic Surgery, Affiliated Hospital of Yangzhou University, Yangzhou, P.R. China.
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10
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van den Akker GGH, Chabronova A, Housmans BAC, van der Vloet L, Surtel DAM, Cremers A, Marchand V, Motorin Y, Caron MMJ, Peffers MJ, Welting TJM. TGF-β2 Induces Ribosome Activity, Alters Ribosome Composition and Inhibits IRES-Mediated Translation in Chondrocytes. Int J Mol Sci 2024; 25:5031. [PMID: 38732249 PMCID: PMC11084827 DOI: 10.3390/ijms25095031] [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: 03/12/2024] [Revised: 04/29/2024] [Accepted: 05/01/2024] [Indexed: 05/13/2024] Open
Abstract
Alterations in cell fate are often attributed to (epigenetic) regulation of gene expression. An emerging paradigm focuses on specialized ribosomes within a cell. However, little evidence exists for the dynamic regulation of ribosome composition and function. Here, we stimulated a chondrocytic cell line with transforming growth factor beta (TGF-β2) and mapped changes in ribosome function, composition and ribosomal RNA (rRNA) epitranscriptomics. 35S Met/Cys incorporation was used to evaluate ribosome activity. Dual luciferase reporter assays were used to assess ribosomal modus. Ribosomal RNA expression and processing were determined by RT-qPCR, while RiboMethSeq and HydraPsiSeq were used to determine rRNA modification profiles. Label-free protein quantification of total cell lysates, isolated ribosomes and secreted proteins was done by LC-MS/MS. A three-day TGF-β2 stimulation induced total protein synthesis in SW1353 chondrocytic cells and human articular chondrocytes. Specifically, TGF-β2 induced cap-mediated protein synthesis, while IRES-mediated translation was not (P53 IRES) or little affected (CrPv IGR and HCV IRES). Three rRNA post-transcriptional modifications (PTMs) were affected by TGF-β2 stimulation (18S-Gm1447 downregulated, 18S-ψ1177 and 28S-ψ4598 upregulated). Proteomic analysis of isolated ribosomes revealed increased interaction with eIF2 and tRNA ligases and decreased association of eIF4A3 and heterogeneous nuclear ribonucleoprotein (HNRNP)s. In addition, thirteen core ribosomal proteins were more present in ribosomes from TGF-β2 stimulated cells, albeit with a modest fold change. A prolonged stimulation of chondrocytic cells with TGF-β2 induced ribosome activity and changed the mode of translation. These functional changes could be coupled to alterations in accessory proteins in the ribosomal proteome.
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Affiliation(s)
- Guus G. H. van den Akker
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Research School CAPHRI, Faculty of Healthy Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.C.); (M.M.J.C.); (T.J.M.W.)
| | - Alzbeta Chabronova
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Research School CAPHRI, Faculty of Healthy Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.C.); (M.M.J.C.); (T.J.M.W.)
- Department of Musculoskeletal Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK
| | - Bas A. C. Housmans
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Research School CAPHRI, Faculty of Healthy Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.C.); (M.M.J.C.); (T.J.M.W.)
| | - Laura van der Vloet
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Research School CAPHRI, Faculty of Healthy Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.C.); (M.M.J.C.); (T.J.M.W.)
| | - Don A. M. Surtel
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Research School CAPHRI, Faculty of Healthy Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.C.); (M.M.J.C.); (T.J.M.W.)
| | - Andy Cremers
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Research School CAPHRI, Faculty of Healthy Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.C.); (M.M.J.C.); (T.J.M.W.)
| | - Virginie Marchand
- UAR2008 IBSLor CNRS-INSERM, Université de Lorraine, BioPole, F54000 Nancy, France; (V.M.); (Y.M.)
| | - Yuri Motorin
- UAR2008 IBSLor CNRS-INSERM, Université de Lorraine, BioPole, F54000 Nancy, France; (V.M.); (Y.M.)
- UMR7365 IMoPA, CNRS, Université de Lorraine, BioPole, F54000 Nancy, France
| | - Marjolein M. J. Caron
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Research School CAPHRI, Faculty of Healthy Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.C.); (M.M.J.C.); (T.J.M.W.)
| | - Mandy J. Peffers
- Department of Musculoskeletal Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK
| | - Tim J. M. Welting
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Research School CAPHRI, Faculty of Healthy Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.C.); (M.M.J.C.); (T.J.M.W.)
- Laboratory of Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University Medical Center +, 6229 HX Maastricht, The Netherlands
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11
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Epanomeritakis IE, Khan WS. Adipose-derived regenerative therapies for the treatment of knee osteoarthritis. World J Stem Cells 2024; 16:324-333. [PMID: 38690511 PMCID: PMC11056639 DOI: 10.4252/wjsc.v16.i4.324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/15/2024] [Accepted: 03/01/2024] [Indexed: 04/25/2024] Open
Abstract
Knee osteoarthritis is a degenerative condition with a significant disease burden and no disease-modifying therapy. Definitive treatment ultimately requires joint replacement. Therapies capable of regenerating cartilage could significantly reduce financial and clinical costs. The regenerative potential of mesenchymal stromal cells (MSCs) has been extensively studied in the context of knee osteoarthritis. This has yielded promising results in human studies, and is likely a product of immunomodulatory and chondroprotective biomolecules produced by MSCs in response to inflammation. Adipose-derived MSCs (ASCs) are becoming increasingly popular owing to their relative ease of isolation and high proliferative capacity. Stromal vascular fraction (SVF) and micro-fragmented adipose tissue (MFAT) are produced by the enzymatic and mechanical disruption of adipose tissue, respectively. This avoids expansion of isolated ASCs ex vivo and their composition of heterogeneous cell populations, including immune cells, may potentiate the reparative function of ASCs. In this editorial, we comment on a multicenter randomized trial regarding the efficacy of MFAT in treating knee osteoarthritis. We discuss the study's findings in the context of emerging evidence regarding adipose-derived regenerative therapies. An underlying mechanism of action of ASCs is proposed while drawing important distinctions between the properties of isolated ASCs, SVF, and MFAT.
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Affiliation(s)
- Ilias E Epanomeritakis
- Division of Trauma and Orthopaedic Surgery, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Wasim S Khan
- Division of Trauma and Orthopaedic Surgery, Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
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12
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Turnbull J, Jha RR, Barrett DA, Valdes AM, Alderson J, Williams A, Vincent TL, Watt FE, Chapman V. The Effect of Acute Knee Injuries and Related Knee Surgery on Serum Levels of Pro- and Anti-inflammatory Lipid Mediators and Their Associations With Knee Symptoms. Am J Sports Med 2024; 52:987-997. [PMID: 38406872 PMCID: PMC10943603 DOI: 10.1177/03635465241228209] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 11/29/2023] [Indexed: 02/27/2024]
Abstract
BACKGROUND Despite an acute knee injury being a major risk factor for osteoarthritis, the factors that initiate and maintain this risk of longer-term knee symptoms are poorly understood. Bioactive lipids derived from omega-3 and -6 polyunsaturated fatty acids have key roles in the regulation of the inflammatory response and have been linked to joint damage and osteoarthritis pain in translational models. HYPOTHESIS There would be associations between systemic levels of bioactive lipids and knee symptoms longitudinally after an acute knee injury and related knee surgery. STUDY DESIGN Controlled laboratory study. METHODS This study analyzed a subset of young, active adults who had sustained an acute knee injury (recruited via a surgical care pathway) and healthy age- and sex-matched controls. Surgery, if performed, was conducted after the baseline serum sample was taken and before the 3-month and 2-year visits. Liquid chromatography-tandem mass spectrometry of 41 bioactive lipids was carried out in sera of (1) 47 injured participants (median age, 28 years) collected at baseline (median, 24 days after injury), 3 months, and 2 years, along with the Knee injury and Osteoarthritis Outcome Score, and (2) age- and sex-matched controls. RESULTS Levels of the omega-3 polyunsaturated fatty acids eicosapentaenoic acid (P≤ .0001) and docosahexaenoic acid (P≤ .0001) and the pro-resolving lipid mediators 17- and 14-hydroxydocosahexaenoic acid, and 18-hydroxyeicosapentaenoic acid were all significantly greater at baseline in injured participants compared with the later time points and also higher than in healthy controls (P = .0019 and P≤ .0001, respectively). Levels of pro-inflammatory prostaglandins E2 and D2, leukotriene B4, and thromboxane B2 were significantly lower at baseline compared with the later time points. Higher levels of 8,9-, 11,12-, and 14,15-dihydroxyeicosatrienoic acid (DHET) were cross-sectionally associated with more severe knee pain/symptoms according to the Knee injury and Osteoarthritis Outcome Score at 2 years (P = .0004, R2 = 0.251; P = .0002, R2 = 0.278; and P = .0012, R2 = 0.214, respectively). CONCLUSION The profile of pro-resolving versus pro-inflammatory lipids at baseline suggests an initial activation of pro-resolution pathways, followed by the later activation of pro-inflammatory pathways. CLINICAL RELEVANCE In this largely surgically managed cohort, the association of soluble epoxide hydrolase metabolites, the DHETs, with more severe knee symptoms at 2 years provides a rationale for further investigation into the role of this pathway in persisting knee symptoms in this population, including potential therapeutic strategies.
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Affiliation(s)
- James Turnbull
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
- Centre for Analytical Bioscience, Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, Nottingham, UK
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Rakesh R. Jha
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
- Centre for Analytical Bioscience, Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - David A. Barrett
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
- Centre for Analytical Bioscience, Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Ana M. Valdes
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
- Injury, Recovery, and Inflammation Sciences, School of Medicine, University of Nottingham, Nottingham, UK
| | - Jennifer Alderson
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Andrew Williams
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
- Fortius Clinic, London, UK
| | - Tonia L. Vincent
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Fiona E. Watt
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
- Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Victoria Chapman
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
- School of Life Sciences, University of Nottingham, Nottingham, UK
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13
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Ansari M, Darvishi A, Sabzevari A. A review of advanced hydrogels for cartilage tissue engineering. Front Bioeng Biotechnol 2024; 12:1340893. [PMID: 38390359 PMCID: PMC10881834 DOI: 10.3389/fbioe.2024.1340893] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 01/29/2024] [Indexed: 02/24/2024] Open
Abstract
With the increase in weight and age of the population, the consumption of tobacco, inappropriate foods, and the reduction of sports activities in recent years, bone and joint diseases such as osteoarthritis (OA) have become more common in the world. From the past until now, various treatment strategies (e.g., microfracture treatment, Autologous Chondrocyte Implantation (ACI), and Mosaicplasty) have been investigated and studied for the prevention and treatment of this disease. However, these methods face problems such as being invasive, not fully repairing the tissue, and damaging the surrounding tissues. Tissue engineering, including cartilage tissue engineering, is one of the minimally invasive, innovative, and effective methods for the treatment and regeneration of damaged cartilage, which has attracted the attention of scientists in the fields of medicine and biomaterials engineering in the past several years. Hydrogels of different types with diverse properties have become desirable candidates for engineering and treating cartilage tissue. They can cover most of the shortcomings of other treatment methods and cause the least secondary damage to the patient. Besides using hydrogels as an ideal strategy, new drug delivery and treatment methods, such as targeted drug delivery and treatment through mechanical signaling, have been studied as interesting strategies. In this study, we review and discuss various types of hydrogels, biomaterials used for hydrogel manufacturing, cartilage-targeting drug delivery, and mechanosignaling as modern strategies for cartilage treatment.
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Affiliation(s)
- Mojtaba Ansari
- Department of Biomedical Engineering, Meybod University, Meybod, Iran
| | - Ahmad Darvishi
- Department of Biomedical Engineering, Meybod University, Meybod, Iran
| | - Alireza Sabzevari
- Department of Biomedical Engineering, Meybod University, Meybod, Iran
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14
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De Leon-Oliva D, Boaru DL, Perez-Exposito RE, Fraile-Martinez O, García-Montero C, Diaz R, Bujan J, García-Honduvilla N, Lopez-Gonzalez L, Álvarez-Mon M, Saz JV, de la Torre B, Ortega MA. Advanced Hydrogel-Based Strategies for Enhanced Bone and Cartilage Regeneration: A Comprehensive Review. Gels 2023; 9:885. [PMID: 37998975 PMCID: PMC10670584 DOI: 10.3390/gels9110885] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/06/2023] [Accepted: 11/07/2023] [Indexed: 11/25/2023] Open
Abstract
Bone and cartilage tissue play multiple roles in the organism, including kinematic support, protection of organs, and hematopoiesis. Bone and, above all, cartilaginous tissues present an inherently limited capacity for self-regeneration. The increasing prevalence of disorders affecting these crucial tissues, such as bone fractures, bone metastases, osteoporosis, or osteoarthritis, underscores the urgent imperative to investigate therapeutic strategies capable of effectively addressing the challenges associated with their degeneration and damage. In this context, the emerging field of tissue engineering and regenerative medicine (TERM) has made important contributions through the development of advanced hydrogels. These crosslinked three-dimensional networks can retain substantial amounts of water, thus mimicking the natural extracellular matrix (ECM). Hydrogels exhibit exceptional biocompatibility, customizable mechanical properties, and the ability to encapsulate bioactive molecules and cells. In addition, they can be meticulously tailored to the specific needs of each patient, providing a promising alternative to conventional surgical procedures and reducing the risk of subsequent adverse reactions. However, some issues need to be addressed, such as lack of mechanical strength, inconsistent properties, and low-cell viability. This review describes the structure and regeneration of bone and cartilage tissue. Then, we present an overview of hydrogels, including their classification, synthesis, and biomedical applications. Following this, we review the most relevant and recent advanced hydrogels in TERM for bone and cartilage tissue regeneration.
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Affiliation(s)
- Diego De Leon-Oliva
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
| | - Diego Liviu Boaru
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
| | - Roque Emilio Perez-Exposito
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Service of Traumatology of University Hospital Ramón y Cajal, 28034 Madrid, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
| | - Cielo García-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
| | - Raul Diaz
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Julia Bujan
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
| | - Laura Lopez-Gonzalez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
- Immune System Diseases-Rheumatology Service, Hospital Universitario Principe de Asturias, 28801 Alcala de Henares, Spain
| | - Jose V. Saz
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
- Department of Biomedicine and Biotechnology, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Basilio de la Torre
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
- Service of Traumatology of University Hospital Ramón y Cajal, 28034 Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Miguel A. Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (D.D.L.-O.); (D.L.B.); (R.E.P.-E.); (O.F.-M.); (C.G.-M.); (J.B.); (N.G.-H.); (L.L.-G.); (M.Á.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (R.D.); (J.V.S.); (B.d.l.T.)
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15
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Drummond SP, Bartnik E, Kouvatsos N, Scott JL, Dyer DP, Thomson JM, Price AJ, Anand S, Biant LC, Leeuw T, Herrmann M, Milner CM, Day AJ. The recombinant Link module of human TSG-6 suppresses cartilage damage in models of osteoarthritis: A potential disease-modifying OA drug. Osteoarthritis Cartilage 2023; 31:1353-1364. [PMID: 37257556 DOI: 10.1016/j.joca.2023.05.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 05/09/2023] [Accepted: 05/22/2023] [Indexed: 06/02/2023]
Abstract
OBJECTIVE To investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA. DESIGN Knee articular cartilages from OA patients were analyzed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module (Link_TSG6) on cytokine-induced degradation of OA cartilage explants were compared. Human mesenchymal stem/stromal cell-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β-, or TNF-stimulated ADAMTS4, ADAMTS5, and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model; cartilage damage and tactile allodynia were assessed. RESULTS TSG-6 is predominantly associated with chondrocytes in regions of cartilage damage where high TSG-6 expression aligns with low MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants;>50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Link_TSG6 also displayed more potent effects in 3D pellet cultures, suppressing ADAMTS4, ADAMTS5, and MMP13 gene expression, which was consistent with reduced aggrecanase and collagenase activities in explant cultures. Link_TSG6 treatment reduced touch-evoked pain behavior and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA. CONCLUSIONS Link_TSG6 has enhanced chondroprotective activity compared to the full-length TSG-6 protein and shows potential as a disease modifying OA drug via its inhibition of aggrecanase and collagenase activity.
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Affiliation(s)
- Sheona P Drummond
- Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Eckart Bartnik
- Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt, Germany
| | - Nikolaos Kouvatsos
- Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Jenny L Scott
- Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Douglas P Dyer
- Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Jennifer M Thomson
- Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Andrew J Price
- Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Sanjay Anand
- Department of Orthopaedics, Stepping Hill Hospital, Stockport, UK
| | - Leela C Biant
- Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Manchester Orthopaedic Centre, Manchester University Hospitals Foundation Trust, Manchester, UK
| | - Thomas Leeuw
- Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt, Germany
| | | | - Caroline M Milner
- Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
| | - Anthony J Day
- Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Faculty of Biology Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
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16
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Zhu L, Vincent TL. Genome-Wide Association Studies to Drug: Identifying Retinoic Acid Metabolism Blocking Agents to Suppress Mechanoflammation in Osteoarthritis. DNA Cell Biol 2023; 42:527-531. [PMID: 37418291 DOI: 10.1089/dna.2023.0197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/08/2023] Open
Abstract
Osteoarthritis (OA) is a highly prevalent debilitating joint disease for which there are currently no licensed disease-modifying treatments. The pathogenesis of OA is complex, involving genetic, mechanical, biochemical, and environmental factors. Cartilage injury, arguably the most important driving factor in OA development, is able to activate both protective and inflammatory pathways within the tissue. Recently, >100 genetic risk variants for OA have been identified through Genome Wide Association Studies, which provide a powerful tool to validate existing putative disease pathways and discover new ones. Using such an approach, hypomorphic variants within the aldehyde dehydrogenase 1 family member A2 (ALDH1A2) gene were shown to be associated with increased risk of severe hand OA. ALDH1A2 encodes the enzyme that synthesizes all-trans retinoic acid (atRA), an intracellular signaling molecule. This review summarizes the influence of the genetic variants on expression and function of ALDH1A2 in OA cartilage, its role in the mechanical injury response of cartilage, and its potent anti-inflammatory effect after cartilage injury. In doing so it identifies atRA metabolism-blocking agents as potential treatments for suppressing mechanoflammation in OA.
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Affiliation(s)
- Linyi Zhu
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Tonia L Vincent
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
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Autologous Collagen-Induced Chondrogenesis: From Bench to Clinical Development. Medicina (B Aires) 2023; 59:medicina59030530. [PMID: 36984531 PMCID: PMC10056533 DOI: 10.3390/medicina59030530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/04/2023] [Accepted: 03/07/2023] [Indexed: 03/11/2023] Open
Abstract
Microfracture is a common technique that uses bone marrow components to stimulate cartilage regeneration. However, the clinical results of microfracture range from poor to good. To enhance cartilage healing, several reinforcing techniques have been developed, including porcine-derived collagen scaffold, hyaluronic acid, and chitosan. Autologous collagen-induced chondrogenesis (ACIC) is a single-step surgical technique for cartilage regeneration that combines gel-type atelocollagen scaffolding with microfracture. Even though ACIC is a relatively new technique, literature show excellent clinical results. In addition, all procedures of ACIC are performed arthroscopically, which is increasing in preference among surgeons and patients. The ACIC technique also is called the Shetty–Kim technique because it was developed from the works of A.A. Shetty and S.J. Kim. This is an up-to-date review of the history of ACIC.
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18
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Hu Y, Li K, Swahn H, Ordoukhanian P, Head SR, Natarajan P, Woods AK, Joseph SB, Johnson KA, Lotz MK. Transcriptomic analyses of joint tissues during osteoarthritis development in a rat model reveal dysregulated mechanotransduction and extracellular matrix pathways. Osteoarthritis Cartilage 2023; 31:199-212. [PMID: 36354073 PMCID: PMC9892293 DOI: 10.1016/j.joca.2022.10.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 09/20/2022] [Accepted: 10/03/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Transcriptomic changes in joint tissues during the development of osteoarthritis (OA) are of interest for the discovery of biomarkers and mechanisms of disease. The objective of this study was to use the rat medial meniscus transection (MMT) model to discover stage and tissue-specific transcriptomic changes. DESIGN Sham or MMT surgeries were performed in mature rats. Cartilage, menisci and synovium were scored for histopathological changes at 2, 4 and 6 weeks post-surgery and processed for RNA-sequencing. Differentially expressed genes (DEG) were used to identify pathways and mechanisms. Published transcriptomic datasets from animal models and human OA were used to confirm and extend present findings. RESULTS The total number of DEGs was already high at 2 weeks (723 in meniscus), followed by cartilage (259) and synovium (42) and declined to varying degrees in meniscus and synovium but increased in cartilage at 6 weeks. The most upregulated genes included tenascins. The 'response to mechanical stimulus' and extracellular matrix-related pathways were enriched in both cartilage and meniscus. Pathways that were enriched in synovium at 4 weeks indicate processes related to synovial hyperplasia and fibrosis. Synovium also showed upregulation of IL-11 and several MMPs. The mechanical stimulus pathway included upregulation of the mechanoreceptors PIEZO1, PIEZO2 and TRPV4 and nerve growth factor. Analysis of data from prior RNA-sequencing studies of animal models and human OA support these findings. CONCLUSION These results indicate several shared pathways that are affected during OA in cartilage and meniscus and support the role of mechanotransduction and other pathways in OA pathogenesis.
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Affiliation(s)
- Y Hu
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, 92037, USA; Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China
| | - K Li
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, 92037, USA
| | - H Swahn
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, 92037, USA
| | - P Ordoukhanian
- Center for Computational Biology & Bioinformatics and Genomics Core, Scripps Research, La Jolla, CA, 92037, USA
| | - S R Head
- Center for Computational Biology & Bioinformatics and Genomics Core, Scripps Research, La Jolla, CA, 92037, USA
| | - P Natarajan
- Center for Computational Biology & Bioinformatics and Genomics Core, Scripps Research, La Jolla, CA, 92037, USA
| | - A K Woods
- Calibr, a Division of Scripps Research, La Jolla, CA, 92037, USA
| | - S B Joseph
- Calibr, a Division of Scripps Research, La Jolla, CA, 92037, USA
| | - K A Johnson
- Calibr, a Division of Scripps Research, La Jolla, CA, 92037, USA
| | - M K Lotz
- Department of Molecular Medicine, Scripps Research, La Jolla, CA, 92037, USA.
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Thudium CS, Engstrøm A, Bay-Jensen AC, Frederiksen P, Jansen N, De Zwart A, van der Leeden M, Dekker J, Lems W, Roorda L, van Spil WE, Van der Esch M. Cartilage tissue turnover increases with high- compared to low-intensity resistance training in patients with knee OA. Arthritis Res Ther 2023; 25:22. [PMID: 36765372 PMCID: PMC9912672 DOI: 10.1186/s13075-023-03000-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/27/2023] [Indexed: 02/12/2023] Open
Abstract
OBJECTIVES To investigate cartilage tissue turnover in response to a supervised 12-week exercise-related joint loading training program followed by a 6-month period of unsupervised training in patients with knee osteoarthritis (OA). To study the difference in cartilage tissue turnover between high- and low-resistance training. METHOD Patients with knee OA were randomized into either high-intensity or low-intensity resistance supervised training (two sessions per week) for 3 months and unsupervised training for 6 months. Blood samples were collected before and after the supervised training period and after the follow-up period. Biomarkers huARGS, C2M, and PRO-C2, quantifying cartilage tissue turnover, were measured by ELISA. Changes in biomarker levels over time within and between groups were analyzed using linear mixed models with baseline values as covariates. RESULTS huARGS and C2M levels increased after training and at follow-up in both low- and high-intensity exercise groups. No changes were found in PRO-C2. The huARGS level in the high-intensity resistance training group increased significantly compared to the low-intensity resistance training group after resistance training (p = 0.029) and at follow-up (p = 0.003). CONCLUSION Cartilage tissue turnover and cartilage degradation appear to increase in response to a 3-month exercise-related joint loading training program and at 6-month follow-up, with no evident difference in type II collagen formation. Aggrecan remodeling increased more with high-intensity resistance training than with low-intensity exercise. These exploratory biomarker results, indicating more cartilage degeneration in the high-intensity group, in combination with no clinical outcome differences of the VIDEX study, may argue against high-intensity training.
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Affiliation(s)
- Christian S. Thudium
- grid.436559.80000 0004 0410 881XImmunoscience, Nordic Bioscience, Herlev, Denmark
| | - Amalie Engstrøm
- grid.436559.80000 0004 0410 881XImmunoscience, Nordic Bioscience, Herlev, Denmark ,grid.5254.60000 0001 0674 042XFaculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Peder Frederiksen
- grid.436559.80000 0004 0410 881XImmunoscience, Nordic Bioscience, Herlev, Denmark
| | - Nuria Jansen
- grid.418029.60000 0004 0624 3484Reade Centre for Rehabilitation and Rheumatology, Amsterdam, the Netherlands
| | - Arjan De Zwart
- grid.418029.60000 0004 0624 3484Reade Centre for Rehabilitation and Rheumatology, Amsterdam, the Netherlands
| | - Marike van der Leeden
- grid.418029.60000 0004 0624 3484Reade Centre for Rehabilitation and Rheumatology, Amsterdam, the Netherlands ,grid.12380.380000 0004 1754 9227Department of Rehabilitation Medicine, Amsterdam Institute of Public Health, Amsterdam UMC, Vrije Universiteit Amsterdam, de Boelelaan, 1117 Amsterdam, the Netherlands
| | - Joost Dekker
- grid.12380.380000 0004 1754 9227Department of Rehabilitation Medicine, Amsterdam Institute of Public Health, Amsterdam UMC, Vrije Universiteit Amsterdam, de Boelelaan, 1117 Amsterdam, the Netherlands
| | - Willem Lems
- grid.418029.60000 0004 0624 3484Reade Centre for Rehabilitation and Rheumatology, Amsterdam, the Netherlands ,grid.12380.380000 0004 1754 9227Department of Rheumatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Leo Roorda
- grid.418029.60000 0004 0624 3484Reade Centre for Rehabilitation and Rheumatology, Amsterdam, the Netherlands
| | - Willem Evert van Spil
- Dijklander Hospital, Hoorn, the Netherlands ,grid.7692.a0000000090126352University Medical Center Utrecht, Utrecht, the Netherlands
| | - Martin Van der Esch
- grid.418029.60000 0004 0624 3484Reade Centre for Rehabilitation and Rheumatology, Amsterdam, the Netherlands ,grid.431204.00000 0001 0685 7679Centre of Expertise Urban Vitality, Faculty of Health, Amsterdam University of Applied Sciences, Amsterdam, the Netherlands
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20
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Zhu L, Kamalathevan P, Koneva LA, Zarebska JM, Chanalaris A, Ismail H, Wiberg A, Ng M, Muhammad H, Walsby-Tickle J, McCullagh JSO, Watt FE, Sansom SN, Furniss D, Gardiner MD, Vincent TL, Riley N, Spiteri M, McNab I, Little C, Cogswell L, Critchley P, Giele H, Shirley R. Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis. Sci Transl Med 2022; 14:eabm4054. [PMID: 36542696 DOI: 10.1126/scitranslmed.abm4054] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.
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Affiliation(s)
- Linyi Zhu
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - Pragash Kamalathevan
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - Lada A Koneva
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - Jadwiga Miotla Zarebska
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - Anastasios Chanalaris
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - Heba Ismail
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
- Healthy Lifespan Institute (HELSI) and Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
| | - Akira Wiberg
- Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Michael Ng
- Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Hayat Muhammad
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - John Walsby-Tickle
- Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
| | - James S O McCullagh
- Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
| | - Fiona E Watt
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK
| | - Stephen N Sansom
- Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - Dominic Furniss
- Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Matthew D Gardiner
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
| | - Tonia L Vincent
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK
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21
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Dynamic compression inhibits cytokine-mediated type II collagen degradation. OSTEOARTHRITIS AND CARTILAGE OPEN 2022; 4:100292. [DOI: 10.1016/j.ocarto.2022.100292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 06/22/2022] [Indexed: 11/21/2022] Open
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22
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Lesage R, Ferrao Blanco MN, Narcisi R, Welting T, van Osch GJVM, Geris L. An integrated in silico-in vitro approach for identifying therapeutic targets against osteoarthritis. BMC Biol 2022; 20:253. [PMID: 36352408 PMCID: PMC9648005 DOI: 10.1186/s12915-022-01451-8] [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: 01/28/2022] [Accepted: 10/27/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Without the availability of disease-modifying drugs, there is an unmet therapeutic need for osteoarthritic patients. During osteoarthritis, the homeostasis of articular chondrocytes is dysregulated and a phenotypical transition called hypertrophy occurs, leading to cartilage degeneration. Targeting this phenotypic transition has emerged as a potential therapeutic strategy. Chondrocyte phenotype maintenance and switch are controlled by an intricate network of intracellular factors, each influenced by a myriad of feedback mechanisms, making it challenging to intuitively predict treatment outcomes, while in silico modeling can help unravel that complexity. In this study, we aim to develop a virtual articular chondrocyte to guide experiments in order to rationalize the identification of potential drug targets via screening of combination therapies through computational modeling and simulations. RESULTS We developed a signal transduction network model using knowledge-based and data-driven (machine learning) modeling technologies. The in silico high-throughput screening of (pairwise) perturbations operated with that network model highlighted conditions potentially affecting the hypertrophic switch. A selection of promising combinations was further tested in a murine cell line and primary human chondrocytes, which notably highlighted a previously unreported synergistic effect between the protein kinase A and the fibroblast growth factor receptor 1. CONCLUSIONS Here, we provide a virtual articular chondrocyte in the form of a signal transduction interactive knowledge base and of an executable computational model. Our in silico-in vitro strategy opens new routes for developing osteoarthritis targeting therapies by refining the early stages of drug target discovery.
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Affiliation(s)
- Raphaëlle Lesage
- Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium
- Biomechanics Section, KU Leuven, Leuven, Belgium
| | - Mauricio N Ferrao Blanco
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Roberto Narcisi
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Tim Welting
- Orthopedic Surgery Department, UMC+, Maastricht, the Netherlands
| | - Gerjo J V M van Osch
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Department of Otorhinolaryngology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Department of Biomechanical Engineering, Delft University of Technology, Delft, the Netherlands
| | - Liesbet Geris
- Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium.
- Biomechanics Section, KU Leuven, Leuven, Belgium.
- GIGA In silico Medicine, University of Liège, Liège, Belgium.
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23
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Reiter MP, Ward SH, Perry B, Mann A, Freeman JW, Tiku ML. Intra-articular injection of epigallocatechin (EGCG) crosslinks and alters biomechanical properties of articular cartilage, a study via nanoindentation. PLoS One 2022; 17:e0276626. [PMID: 36282841 PMCID: PMC9595553 DOI: 10.1371/journal.pone.0276626] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022] Open
Abstract
Osteoarthritis and rheumatoid arthritis are debilitating conditions, affecting millions of people. Both osteoarthritis and rheumatoid arthritis degrade the articular cartilage (AC) at the ends of long bones, resulting in weakened tissue prone to further damage. This degradation impairs the cartilage’s mechanical properties leading to areas of thinned cartilage and exposed bone which compromises the integrity of the joint. No preventative measures exist for joint destruction. Discovering a way to slow the degradation of AC or prevent it would slow the painful progression of the disease, allowing millions to live pain-free. Recently, that the articular injection of the polyphenol epigallocatechin-gallate (EGCG) slows AC damage in an arthritis rat model. It was suggested that EGCG crosslinks AC and makes it resistant to degradation. However, direct evidence that intraarticular injection of EGCG crosslinks cartilage collagen and changes its compressive properties are not known. The aim of this study was to investigate the effects of intraarticular injection of EGCG induced biomechanical properties of AC. We hypothesize that in vivo exposure EGCG will bind and crosslink to AC collagen and alter its biomechanical properties. We developed a technique of nano-indentation to investigate articular cartilage properties by measuring cartilage compressive properties and quantifying differences due to EGCG exposure. In this study, the rat knee joint was subjected to a series of intraarticular injections of EGCG and contralateral knee joint was injected with saline. After the injections animals were sacrificed, and the knees were removed and tested in an anatomically relevant model of nanoindentation. All mechanical data was normalized to the measurements in the contralateral knee to better compare data between the animals. The data demonstrated significant increases for reduced elastic modulus (57.5%), hardness (83.2%), and stiffness (17.6%) in cartilage treated with injections of EGCG normalized to those treated with just saline solution when compared to baseline subjects without injections, with a significance level of alpha = 0.05. This data provides evidence that EGCG treated cartilage yields a strengthened cartilage matrix as compared to AC from the saline injected knees. These findings are significant because the increase in cartilage biomechanics will translate into resistance to degradation in arthritis. Furthermore, the data suggest for the first time that it is possible to strengthen the articular cartilage by intraarticular injections of polyphenols. Although this data is preliminary, it suggests that clinical applications of EGCG treated cartilage could yield strengthened tissue with the potential to resist or compensate for matrix degradation caused by arthritis.
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Affiliation(s)
- Mary Pat Reiter
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
| | - Shawn H. Ward
- Department of Materials Science and Engineering, Rutgers University, Piscataway, New Jersey, United States of America
| | - Barbara Perry
- Department of Orthopedic Surgery, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America
| | - Adrian Mann
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
- Department of Materials Science and Engineering, Rutgers University, Piscataway, New Jersey, United States of America
| | - Joseph W. Freeman
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, United States of America
- * E-mail:
| | - Moti L. Tiku
- Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America
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24
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Hosokawa H, Akagi R, Watanabe S, Horii M, Shinohara M, Mikami Y, Toguchi K, Kimura S, Yamaguchi S, Ohtori S, Sasho T. Nuclear receptor subfamily 1 group D member 1 in the pathology of obesity-induced osteoarthritis progression. J Orthop Res 2022; 41:930-941. [PMID: 36102152 DOI: 10.1002/jor.25440] [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: 04/10/2022] [Revised: 07/28/2022] [Accepted: 09/02/2022] [Indexed: 02/04/2023]
Abstract
Mechanical overload and chemical factors are both related to obesity-induced progression of knee osteoarthritis. The circadian rhythm is related to the development of metabolic syndrome and the progression of osteoarthritis, and the core clock genes nuclear receptor subfamily 1 group D member 1 (NR1D1) and brain and muscle arnt-like protein 1 (BMAL1) are dysregulated in cartilage from patients with osteoarthritis. Here, we focused on NR1D1 and investigated osteoarthritis-related changes and gene expression in a mouse model of diet-induced obesity. A high-fat diet was provided to C57BL6/J mice, and changes in body weight, blood lipids, and gene expression were investigated. Destabilization of the medial meniscus or sham surgery was performed on mice fed a high-fat diet or normal diet, and histological osteoarthritis-related changes and NR1D1 expression were investigated. The effects of the NR1D1 agonist SR9009 were also assessed. Mice fed a high-fat diet developed significant obesity and dyslipidemia. Nr1d1 and Bmal1 gene expression levels decreased in the liver and knee joints. Moreover, increased osteoarthritis progression and decreased NR1D1 protein expression were observed in high-fat diet-fed mice after surgical osteoarthritis induction. SR9009 decreased the progression of obesity, dyslipidemia, and osteoarthritis. Overall, obesity and dyslipidemia induced by the high-fat diet led to osteoarthritis progression and decreased NR1D1 expression. Thus, NR1D1 may play an important role in obesity-induced osteoarthritis.
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Affiliation(s)
- Hiroaki Hosokawa
- Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba, Japan.,Center for Preventive Medicine, Musculoskeletal Disease and Pain, Chiba University, Chiba, Japan
| | - Ryuichiro Akagi
- Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba, Japan
| | - Shotaro Watanabe
- Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba, Japan.,Center for Preventive Medicine, Musculoskeletal Disease and Pain, Chiba University, Chiba, Japan
| | - Manato Horii
- Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba, Japan
| | - Masashi Shinohara
- Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba, Japan
| | - Yukio Mikami
- Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba, Japan
| | - Kaoru Toguchi
- Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba, Japan
| | - Seiji Kimura
- Department of Orthopaedic Surgery, Center for Advanced Joint Function and Reconstructive Spine Surgery Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Satoshi Yamaguchi
- Graduate School of Global and Transdisciplinary Studies, Chiba University, Chiba, Japan
| | - Seiji Ohtori
- Department of Orthopaedic Surgery, School of Medicine, Chiba University, Chiba, Japan
| | - Takahisa Sasho
- Center for Preventive Medicine, Musculoskeletal Disease and Pain, Chiba University, Chiba, Japan
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25
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Vincent TL, McClurg O, Troeberg L. The Extracellular Matrix of Articular Cartilage Controls the Bioavailability of Pericellular Matrix-Bound Growth Factors to Drive Tissue Homeostasis and Repair. Int J Mol Sci 2022; 23:6003. [PMID: 35682681 PMCID: PMC9181404 DOI: 10.3390/ijms23116003] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 11/24/2022] Open
Abstract
The extracellular matrix (ECM) has long been regarded as a packing material; supporting cells within the tissue and providing tensile strength and protection from mechanical stress. There is little surprise when one considers the dynamic nature of many of the individual proteins that contribute to the ECM, that we are beginning to appreciate a more nuanced role for the ECM in tissue homeostasis and disease. Articular cartilage is adapted to be able to perceive and respond to mechanical load. Indeed, physiological loads are essential to maintain cartilage thickness in a healthy joint and excessive mechanical stress is associated with the breakdown of the matrix that is seen in osteoarthritis (OA). Although the trigger by which increased mechanical stress drives catabolic pathways remains unknown, one mechanism by which cartilage responds to increased compressive load is by the release of growth factors that are sequestered in the pericellular matrix. These are heparan sulfate-bound growth factors that appear to be largely chondroprotective and displaced by an aggrecan-dependent sodium flux. Emerging evidence suggests that the released growth factors act in a coordinated fashion to drive cartilage repair. Thus, we are beginning to appreciate that the ECM is the key mechano-sensor and mechano-effector in cartilage, responsible for directing subsequent cellular events of relevance to joint health and disease.
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Affiliation(s)
- Tonia L. Vincent
- Centre for OA Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
| | - Oliver McClurg
- Norwich Medical School, University of East Anglia, Norwich, Norwich NR4 7UQ, UK; (O.M.); (L.T.)
| | - Linda Troeberg
- Norwich Medical School, University of East Anglia, Norwich, Norwich NR4 7UQ, UK; (O.M.); (L.T.)
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Lamuedra A, Gratal P, Calatrava L, Ruiz-Perez VL, Palencia-Campos A, Portal-Núñez S, Mediero A, Herrero-Beaumont G, Largo R. Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify cartilage damage in osteoarthritis. FASEB J 2022; 36:e22258. [PMID: 35334131 DOI: 10.1096/fj.202101791rr] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/21/2022] [Accepted: 03/07/2022] [Indexed: 12/16/2022]
Abstract
Chondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic-like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA-like cartilage lesions, whereas its downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis-van Creveld syndrome skeletal dysplasia. Since Ellis-van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout (EvccKO ) model of OA. For this purpose, OA was induced by surgical knee destabilization in wild-type (WT) and EvccKO adult mice, and healthy WT mice were used as controls (n = 10 knees/group). Hypertrophic markers and Hh genes were measured by qRT-PCR, and metalloproteinases (MMP) levels assessed by western blot. Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL-1 beta as an inflammatory insult. Our results showed that tamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not ameliorate cartilage damage in DMM-EvccKO mice. Hh pathway inhibition did not modify the expression of proinflammatory mediators induced by IL-1 beta in human OA chondrocytes in culture. We found that hypertrophic-IHH-and inflammatory-COX-2-markers co-localized in OA cartilage samples. We concluded that tamoxifen induced inactivation of Evc partially prevented chondrocyte hypertrophy in DMM-EvccKO mice, but it did not ameliorate cartilage damage. Overall, our results suggest that chondrocyte hypertrophy per se is not a pathogenic event in the progression of OA.
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Affiliation(s)
- Ana Lamuedra
- Bone and Joint Research Unit, Service of Rheumatology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, Spain
| | - Paula Gratal
- Bone and Joint Research Unit, Service of Rheumatology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, Spain
| | - Lucía Calatrava
- Instituto de Investigaciones Biomédicas 'Alberto Sols', CSIC-UAM, Madrid, Spain.,CIBER de Enfermedades Raras (CIBERER), ISCIII, Spain
| | - Víctor Luis Ruiz-Perez
- Instituto de Investigaciones Biomédicas 'Alberto Sols', CSIC-UAM, Madrid, Spain.,CIBER de Enfermedades Raras (CIBERER), ISCIII, Spain.,Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IdiPaz-UAM, Madrid, Spain
| | | | - Sergio Portal-Núñez
- Bone Physiopathology Laboratory, Applied Molecular Medicine Institute (IMMA), Universidad San Pablo-CEU, Madrid, Spain
| | - Aránzazu Mediero
- Bone and Joint Research Unit, Service of Rheumatology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, Spain
| | - Gabriel Herrero-Beaumont
- Bone and Joint Research Unit, Service of Rheumatology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, Spain
| | - Raquel Largo
- Bone and Joint Research Unit, Service of Rheumatology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, Spain
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Lin W, Klein J. Hydration Lubrication in Biomedical Applications: From Cartilage to Hydrogels. ACCOUNTS OF MATERIALS RESEARCH 2022; 3:213-223. [PMID: 35243350 PMCID: PMC8886567 DOI: 10.1021/accountsmr.1c00219] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 01/21/2022] [Indexed: 05/11/2023]
Abstract
In the course of evolution, nature has achieved remarkably lubricated surfaces, with healthy articular cartilage in the major (synovial) joints being the prime example, that can last a lifetime as they slide past each other with ultralow friction (friction coefficient μ = the force to slide surfaces past each other/load compressing the surfaces < 0.01) under physiological pressures (up to 10 MPa or more)). Such properties are unmatched by any man-made materials. The precise mechanism of low friction between such sliding cartilage tissues, which is closely related to osteoarthritis (OA), the most widespread joint disease, affecting hundreds of millions worldwide, has been studied for nearly a century, but is still not fully understood. Traditionally, the roles of load bearing by interstitial fluid within the cartilage bulk and that of thin exuded fluid films at the interface between the sliding cartilage surfaces have been proposed as the main lubrication mechanism. More recent work, however, suggests that molecular boundary layers at the surfaces of articular cartilage and other tissues play a major role in their lubrication. In particular, in recent years hydration lubrication has emerged as a new paradigm for boundary lubrication in aqueous media based on subnanometer hydration shells which massively reduce frictional dissipation. The vectors of hydration lubrication include trapped hydrated ions, hydrated surfactants, biological macromolecules, biomimetic polymers, polyelectrolytes and polyzwitterionic brushes, and close-packed layers of phosphatidylcholine (PC) vesicles, all having in common the exposure of highly hydrated groups at the slip plane. Among them, vesicles (or bilayers) of PC lipids, which are the most widespread lipid class in mammals, are exceptionally efficient lubricating elements as a result of the high hydration of the phosphocholine headgroups they expose. Such lipids are ubiquitous in joints, leading to the proposal that macromolecular surface complexes exposing PC bilayers are responsible for the remarkable lubrication of cartilage. Cartilage, comprising ∼70% water, may be considered to be a complex biological hydrogel, and studying the frictional properties of hydrogels may thus provide new insights into its lubrication mechanisms, leading in turn to novel, highly lubricious hydrogels that may be used in a variety of biomedical and other applications. A better understanding of cartilage lubrication could moreover lead to better treatments for OA, for example, through intra-articular injections of appropriate lubricants or through the creation of low-friction hydrogels that may be used as tissue engineering scaffolds for diseased cartilage. In this Account, we begin by introducing the concept and origin of hydration lubrication, extending from the seminal study of lubrication by hydrated simple ions to more complex systems. We then briefly review different modes of lubrication in synovial joints, focusing primarily on boundary lubrication. We consider modes of hydrogel lubrication and different kinds of such low-friction synthetic gels and then focus on cartilage-inspired, boundary-lubricated hydrogels. We conclude by discussing challenges and opportunities.
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Morgan M, Nazemian V, Harrington K, Ivanusic JJ. Mini review: The role of sensory innervation to subchondral bone in osteoarthritis pain. Front Endocrinol (Lausanne) 2022; 13:1047943. [PMID: 36605943 PMCID: PMC9808033 DOI: 10.3389/fendo.2022.1047943] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/30/2022] [Indexed: 01/07/2023] Open
Abstract
Osteoarthritis pain is often thought of as a pain driven by nerves that innervate the soft tissues of the joint, but there is emerging evidence for a role for nerves that innervate the underlying bone. In this mini review we cite evidence that subchondral bone lesions are associated with pain in osteoarthritis. We explore recent studies that provide evidence that sensory neurons that innervate bone are nociceptors that signal pain and can be sensitized in osteoarthritis. Finally, we describe neuronal remodeling of sensory and sympathetic nerves in bone and discuss how these processes can contribute to osteoarthritis pain.
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Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat Rev Rheumatol 2021; 18:67-84. [PMID: 34934171 DOI: 10.1038/s41584-021-00724-w] [Citation(s) in RCA: 178] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2021] [Indexed: 12/12/2022]
Abstract
Mechanical stimuli have fundamental roles in articular cartilage during health and disease. Chondrocytes respond to the physical properties of the cartilage extracellular matrix (ECM) and the mechanical forces exerted on them during joint loading. In osteoarthritis (OA), catabolic processes degrade the functional ECM and the composition and viscoelastic properties of the ECM produced by chondrocytes are altered. The abnormal loading environment created by these alterations propagates cell dysfunction and inflammation. Chondrocytes sense their physical environment via an array of mechanosensitive receptors and channels that activate a complex network of downstream signalling pathways to regulate several cell processes central to OA pathology. Advances in understanding the complex roles of specific mechanosignalling mechanisms in healthy and OA cartilage have highlighted molecular processes that can be therapeutically targeted to interrupt pathological feedback loops. The potential for combining these mechanosignalling targets with the rapidly expanding field of smart mechanoresponsive biomaterials and delivery systems is an emerging paradigm in OA treatment. The continued advances in this field have the potential to enable restoration of healthy mechanical microenvironments and signalling through the development of precision therapeutics, mechanoregulated biomaterials and drug systems in the near future.
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Vincent TL. Post-traumatic OA - are we any closer to prevention? Osteoarthritis Cartilage 2021; 29:1630-1631. [PMID: 34903334 DOI: 10.1016/j.joca.2021.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 10/08/2021] [Indexed: 02/02/2023]
Affiliation(s)
- T L Vincent
- Centre for OA Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, London OX37FY, United Kingdom.
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Solanki K, Shanmugasundaram S, Shetty N, Kim SJ. Articular cartilage repair & joint preservation: A review of the current status of biological approach. J Clin Orthop Trauma 2021; 22:101602. [PMID: 34631411 PMCID: PMC8488240 DOI: 10.1016/j.jcot.2021.101602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/12/2021] [Accepted: 09/12/2021] [Indexed: 01/03/2023] Open
Abstract
The articular cartilage of the joint is the thin viscoelastic layer of the connective tissue. It has a unique anatomy and physiology, which makes the repair of the articular cartilage damage more difficult and challenging due to its limited healing capacity. Increasing knowledge regarding the importance of articular cartilage for joint preservation has led to increased attention on early identification of cartilage damage as well as degeneration in order to delay osteoarthritis. There are various treatment modalities ranging from preventive management, physical therapy, pharmacological, non-pharmacological and surgical treatments exist in current literature. However most of the studies have limited long term follow up and mainly consists of small case series and case reports. This is an up to date concise review discussing the available management options for articular cartilage damage starting to lifestyle modification to pharmacotherapy, physiotherapy, and osteobiologics till various joint preservation techniques that have been in use currently.
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Affiliation(s)
- Ketansinh Solanki
- Department of Arthroscopy and Trauma, Soundarapandian Bone and Joint Hospital, Chennai, India
| | - Saseendar Shanmugasundaram
- Department of Arthroscopy and Cartilage Reconstruction, Apollo Hospital, Muscat, Oman
- Corresponding author.
| | - Neha Shetty
- Kent Knee Unit, Spire Alexandra Hospital, Chatham, Kent, ME5 9PG, UK
| | - Seok-Jung Kim
- Department of Orthopaedic Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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Lee J, Lee J, Lee S, Yoo SA, Kim KM, Kim WU, Cho CS, Yoon CH. Genetic deficiency of nuclear factor of activated T cells 5 attenuates the development of osteoarthritis in mice. Joint Bone Spine 2021; 89:105273. [PMID: 34537377 DOI: 10.1016/j.jbspin.2021.105273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/31/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVES This study is aimed to investigate the role of nuclear factor of activated T cells 5 (NFAT5), originally known as the osmosensitive mammalian transcription factor, in the pathogenesis of osteoarthritis (OA) in mice. METHODS OA was induced in male C57BL/6 (wild-type) and NFAT5 haplo-insufficient (NFAT5+/-) mice via destabilization of the medial meniscus (DMM) surgery. OA severity and synovial inflammation were histologically assessed. Expression of CCL2, inflammatory cytokines, cartilage degrading enzymes was determined in the knee joints and cultured chondrocytes from wild-type and NFAT5+/- mice. RESULTS NFAT5 expression was significantly upregulated in the knee joint of a mouse after DMM surgery. NFAT5 deficiency decreased the severity of synovial inflammation and osteoarthritic changes in cartilage and subchondral bone. Moreover, NFAT5 deficiency also decreased the expression of CCL2, IL-1β, MMP-13, ADMATS-5, and macrophage infiltration in the joint. In cultured chondrocytes, hyperosmolar or IL-1β stimulation significantly enhanced the expression of NFAT5, CCL2, IL-1β, IL-6, and MMP-13, and this effect was abolished in chondrocytes from NFAT5+/- mice. Hyperosmolarity or IL-1β-induced NFAT5 and CCL2 downregulated by inhibiting p38 MAPK, JNK, and ERK pathways. CONCLUSIONS Our results indicate that NFAT5 is a crucial regulator of OA pathogenesis by upregulating CCL2 expression and macrophage recruitment. In chondrocyte, NFAT5 plays an important role in the response to hyperosmolar or IL-1β stimulation. Thus, NFAT5 could be an attractive therapeutic target for OA treatment.
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Affiliation(s)
- Jinhee Lee
- Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Jongmin Lee
- Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Saseong Lee
- Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, 06591, Korea
| | - Seung-Ah Yoo
- Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, 06591, Korea
| | - Ki-Myo Kim
- Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, 06591, Korea
| | - Wan-Uk Kim
- Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, 06591, Korea; Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, 06591, Korea
| | - Chul-Soo Cho
- Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, 06591, Korea
| | - Chong-Hyeon Yoon
- Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
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33
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Garriga C, Goff M, Paterson E, Hrusecka R, Hamid B, Alderson J, Leyland K, Honeyfield L, Greenshields L, Satchithananda K, Lim A, Arden NK, Judge A, Williams A, Vincent TL, Watt FE. Clinical and molecular associations with outcomes at 2 years after acute knee injury: a longitudinal study in the Knee Injury Cohort at the Kennedy (KICK). THE LANCET. RHEUMATOLOGY 2021; 3:e648-e658. [PMID: 34476411 PMCID: PMC8390381 DOI: 10.1016/s2665-9913(21)00116-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Joint injury is a major risk factor for osteoarthritis and provides an opportunity to prospectively examine early processes associated with osteoarthritis. We investigated whether predefined baseline demographic and clinical factors, and protein analytes in knee synovial fluid and in plasma or serum, were associated with clinically relevant outcomes at 2 years after knee injury. METHODS This longitudinal cohort study recruited individuals aged 16-50 years between Nov 1, 2010, and Nov 28, 2014, across six hospitals and clinics in London, UK. Participants were recruited within 8 weeks of having a clinically significant acute knee injury (effusion and structural injury on MRI), which was typically treated surgically. We measured several predefined clinical variables at baseline (eg, time from injury to sampling, extent and type of joint injury, synovial fluid blood staining, presence of effusion, self-reported sex, age, and BMI), and measured 12 synovial fluid and four plasma or serum biomarkers by immunoassay at baseline and 3 months. The primary outcome was Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 2 years, adjusted for baseline score, assessed in all patients. Linear and logistic regression models adjusting for predefined covariates were used to assess associations between baseline variables and 2-year KOOS4. This study is registered with ClinicalTrials.gov, number NCT02667756. FINDINGS We enrolled 150 patients at a median of 17 days (range 1-59, IQR 9-26) after knee injury. 123 (82%) were male, with a median age of 25 years (range 16-50, IQR 21-30). 98 (65%) of 150 participants completed a KOOS4 at 2 (or 3) years after enrolment (50 participants were lost to follow-up and two were withdrawn due to adverse events unrelated to study participation); 77 (51%) participants had all necessary variables available and were included in the core variable adjusted analysis. In the 2-year dataset mean KOOS4 improved from 38 (SD 18) at baseline to 79 (18) at 2 years. Baseline KOOS4, medium-to-large knee effusion, and moderate-to-severe synovial blood staining and their interaction significantly predicted 2-year KOOS4 (n=77; coefficient -20·5, 95% CI -34·8 to -6·18; p=0·0060). The only predefined biomarkers that showed independent associations with 2-year KOOS4 were synovial fluid MCP-1 (n=77; -0·015, 0·027 to -0·004 per change in 1 pg/mL units; p=0·011) and IL-6 (n=77; -0·0005, -0·0009 to -0·0001 per change in 1 pg/mL units; p=0·017). These biomarkers, combined with the interaction of effusion and blood staining, accounted for 39% of outcome variability. Two adverse events occurred that were linked to study participation, both at the time of blood sampling (one presyncopal episode, one tenderness and pain at the site of venepuncture). INTERPRETATION The combination of effusion and haemarthrosis was significantly associated with symptomatic outcomes after acute knee injury. The synovial fluid molecular protein response to acute knee injury (best represented by MCP-1 and IL-6) was independently associated with symptomatic outcomes but not with structural outcomes, with the biomarkers overall playing a minor role relative to clinical predictors. The relationship between symptoms and structure after acute knee injury and their apparent dissociation early in this process need to be better understood to make clinical progress. FUNDING Versus Arthritis, Kennedy Trust for Rheumatology Research, and NIHR Oxford Biomedical Research Centre.
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Affiliation(s)
- Cesar Garriga
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
- Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, UK
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Megan Goff
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Erin Paterson
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Renata Hrusecka
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Benjamin Hamid
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Jennifer Alderson
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
| | - Kirsten Leyland
- NIHR Bristol BRC, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Lesley Honeyfield
- Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Liam Greenshields
- Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Keshthra Satchithananda
- Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
- Department of Radiology, King's College Hospital NHS Foundation Trust, London, UK
| | - Adrian Lim
- Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Nigel K Arden
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
- Centre for Sports, Exercise and Osteoarthritis Research Versus Arthritis, NDORMS, University of Oxford, Oxford, UK
| | - Andrew Judge
- Centre for Statistics in Medicine, NDORMS, University of Oxford, Oxford, UK
- NIHR Bristol BRC, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
- Musculoskeletal Research Unit, University of Bristol, Bristol, UK
| | - Andrew Williams
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
- Fortius Clinic, London, UK
| | - Tonia L Vincent
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
- Department of Rheumatology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Fiona E Watt
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK
- Centre for Sports, Exercise and Osteoarthritis Research Versus Arthritis, NDORMS, University of Oxford, Oxford, UK
- Department of Rheumatology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK
- Department of Immunology and Inflammation, Imperial College London, London, UK
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Kwok AT, Mohamed NS, Plate JF, Yammani RR, Rosas S, Bateman TA, Livingston E, Moore JE, Kerr BA, Lee J, Furdui CM, Tan L, Bouxsein ML, Ferguson VL, Stodieck LS, Zawieja DC, Delp MD, Mao XW, Willey JS. Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents. Sci Rep 2021; 11:10469. [PMID: 34006989 PMCID: PMC8131644 DOI: 10.1038/s41598-021-90010-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 04/15/2021] [Indexed: 11/18/2022] Open
Abstract
Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Rodents exposed to spaceflight or hind limb unloading (HLU) represent unique opportunities to evaluate this question. This study evaluated arthritic changes in the medial knee compartment that bears the highest loads across the knee after actual and simulated spaceflight, and recovery with subsequent full weight-bearing. Cartilage and meniscal degradation in mice were measured via microCT, histology, and proteomics and/or biochemically after: (1) ~ 35 days on the International Space Station (ISS); (2) 13-days aboard the Space Shuttle Atlantis; or (3) 30 days of HLU, followed by a 49-day weight-bearing readaptation with/without exercise. Cartilage degradation post-ISS and HLU occurred at similar spatial locations, the tibial-femoral cartilage-cartilage contact point, with meniscal volume decline. Cartilage and meniscal glycosaminoglycan content were decreased in unloaded mice, with elevated catabolic enzymes (e.g., matrix metalloproteinases), and elevated oxidative stress and catabolic molecular pathway responses in menisci. After the 13-day Shuttle flight, meniscal degradation was observed. During readaptation, recovery of cartilage volume and thickness occurred with exercise. Reduced weight-bearing from either spaceflight or HLU induced an arthritic phenotype in cartilage and menisci, and exercise promoted recovery.
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Affiliation(s)
- Andy T Kwok
- Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Nequesha S Mohamed
- Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Johannes F Plate
- Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Raghunatha R Yammani
- Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.,Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Samuel Rosas
- Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Ted A Bateman
- Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC, USA
| | - Eric Livingston
- Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC, USA
| | - Joseph E Moore
- Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Bethany A Kerr
- Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Jingyun Lee
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.,Proteomics and Metabolomics Shared Resource, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Cristina M Furdui
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.,Proteomics and Metabolomics Shared Resource, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Li Tan
- Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Mary L Bouxsein
- Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Virginia L Ferguson
- Department of Mechanical Engineering, University of Colorado At Boulder, Boulder, CO, USA
| | - Louis S Stodieck
- BioServe Space Technologies, Aerospace Engineering Sciences, University of Colorado At Boulder, Boulder, CO, USA
| | - David C Zawieja
- Department of Medical Physiology, Texas A&M University Medical School, Bryan, TX, USA
| | - Michael D Delp
- Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, FL, USA
| | - Xiao W Mao
- Division of Biomedical Engineering Sciences (BMES), Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA
| | - Jeffrey S Willey
- Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. .,Department of Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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Lin W, Klein J. Recent Progress in Cartilage Lubrication. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2021; 33:e2005513. [PMID: 33759245 DOI: 10.1002/adma.202005513] [Citation(s) in RCA: 200] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 11/23/2020] [Indexed: 05/18/2023]
Abstract
Healthy articular cartilage, covering the ends of bones in major joints such as hips and knees, presents the most efficiently-lubricated surface known in nature, with friction coefficients as low as 0.001 up to physiologically high pressures. Such low friction is indeed essential for its well-being. It minimizes wear-and-tear and hence the cartilage degradation associated with osteoarthritis, the most common joint disease, and, by reducing shear stress on the mechanotransductive, cartilage-embedded chondrocytes (the only cell type in the cartilage), it regulates their function to maintain homeostasis. Understanding the origins of such low friction of the articular cartilage, therefore, is of major importance in order to alleviate disease symptoms, and slow or even reverse its breakdown. This progress report considers the relation between frictional behavior and the cellular mechanical environment in the cartilage, then reviews the mechanism of lubrication in the joints, in particular focusing on boundary lubrication. Following recent advances based on hydration lubrication, a proposed synergy between different molecular components of the synovial joints, acting together in enabling the low friction, has been proposed. Additionally, recent development of natural and bio-inspired lubricants is reviewed.
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Affiliation(s)
- Weifeng Lin
- Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, 76100, Israel
| | - Jacob Klein
- Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, 76100, Israel
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Dudek M, Angelucci C, Pathiranage D, Wang P, Mallikarjun V, Lawless C, Swift J, Kadler KE, Boot-Handford RP, Hoyland JA, Lamande SR, Bateman JF, Meng QJ. Circadian time series proteomics reveals daily dynamics in cartilage physiology. Osteoarthritis Cartilage 2021; 29:739-749. [PMID: 33610821 PMCID: PMC8113022 DOI: 10.1016/j.joca.2021.02.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 01/28/2021] [Accepted: 02/08/2021] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Cartilage in joints such as the hip and knee experiences repeated phases of heavy loading and low load recovery during the 24-h day/night cycle. Our previous work has shown 24 h rhythmic changes in gene expression at transcript level between night and day in wild type mouse cartilage which is lost in a circadian clock knock-out mouse model. However, it remains unknown to what extent circadian rhythms also regulate protein level gene expression in this matrix rich tissue. METHODS We investigated daily changes of protein abundance in mouse femoral head articular cartilage by performing a 48-h time-series LC-MS/MS analysis. RESULTS Out of the 1,177 proteins we identified across all time points, 145 proteins showed rhythmic changes in their abundance within the femoral head cartilage. Among these were molecules that have been implicated in key cartilage functions, including CTGF, MATN1, PAI-1 and PLOD1 & 2. Pathway analysis revealed that protein synthesis, cytoskeleton and glucose metabolism exhibited time-of-day dependent functions. Analysis of published cartilage proteomics datasets revealed that a significant portion of rhythmic proteins were dysregulated in osteoarthritis and/or ageing. CONCLUSIONS Our circadian proteomics study reveals that articular cartilage is a much more dynamic tissue than previously thought, with chondrocytes driving circadian rhythms not only in gene transcription but also in protein abundance. Our results clearly call for the consideration of circadian timing mechanisms not only in cartilage biology, but also in the pathogenesis, treatment strategies and biomarker detection in osteoarthritis.
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Affiliation(s)
- M Dudek
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - C Angelucci
- Murdoch Children's Research Institute and University of Melbourne, Parkville, Victoria, Australia
| | - D Pathiranage
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - P Wang
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - V Mallikarjun
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - C Lawless
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - J Swift
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - K E Kadler
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - R P Boot-Handford
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - J A Hoyland
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; NIHR Manchester Biomedical Research Centre, Central Manchester Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - S R Lamande
- Murdoch Children's Research Institute and University of Melbourne, Parkville, Victoria, Australia
| | - J F Bateman
- Murdoch Children's Research Institute and University of Melbourne, Parkville, Victoria, Australia
| | - Q-J Meng
- Wellcome Centre for Cell Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK.
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Abstract
There is a well-established historical observation that structural joint damage by plain X-ray correlates poorly with symptomatic disease in osteoarthritis (OA). This is often attributed to the inability to visualise soft-tissue pathology within the joint and the recognition of heterogeneous patient factors that drive central pain sensitisation. A major issue is the relative paucity of mechanistic studies in which molecular pathogenesis of pain is interrogated in relation to tissue pathology. Nonetheless, in recent years, three broad approaches have been deployed to attempt to address this: correlative clinical studies of peripheral and central pain outcomes using magnetic resonance imaging, where soft-tissue processes can be visualised; molecular studies on tissue from patients with OA; and careful molecular interrogation of preclinical models of OA across the disease time course. Studies have taken advantage of established clinical molecular targets such as nerve growth factor. Not only is the regulation of nerve growth factor within the joint being used to explore the relationship between tissue pathology and the origins of pain in OA, but it also provides a core model on which other molecules present within the joint can modulate the pain response. In this narrative review, how molecular and pathological tissue change relates to joint pain in OA will be discussed. Finally, a model for how tissue damage may lead to pain over the disease course will be proposed.
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Soul J, Barter MJ, Little CB, Young DA. OATargets: a knowledge base of genes associated with osteoarthritis joint damage in animals. Ann Rheum Dis 2021; 80:376-383. [PMID: 33077471 PMCID: PMC7892386 DOI: 10.1136/annrheumdis-2020-218344] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/21/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To collate the genes experimentally modulated in animal models of osteoarthritis (OA) and compare these data with OA transcriptomics data to identify potential therapeutic targets. METHODS PubMed searches were conducted to identify publications describing gene modulations in animal models. Analysed gene expression data were retrieved from the SkeletalVis database of analysed skeletal microarray and RNA-Seq expression data. A network diffusion approach was used to predict new genes associated with OA joint damage. RESULTS A total of 459 genes were identified as having been modulated in animal models of OA, with ageing and post-traumatic (surgical) models the most prominent. Ninety-eight of the 143 genes (69%) genetically modulated more than once had a consistent effect on OA joint damage severity. Several discrepancies between different studies were identified, providing lessons on interpretation of these data. We used the data collected along with OA gene expression data to expand existing annotations and prioritise the most promising therapeutic targets, which we validated using the latest reported associations. We constructed an online database OATargets to allow researchers to explore the collated data and integrate it with existing OA and skeletal gene expression data. CONCLUSIONS We present a comprehensive survey and online resource for understanding gene regulation of animal model OA pathogenesis.
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Affiliation(s)
- Jamie Soul
- Skeletal Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Matthew J Barter
- Skeletal Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Christopher B Little
- Raymond Purves Bone and Joint Research Laboratories, Kolling Institute, The University of Sydney, St Leonards, New South Wales, Australia
| | - David A Young
- Skeletal Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
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McClurg O, Tinson R, Troeberg L. Targeting Cartilage Degradation in Osteoarthritis. Pharmaceuticals (Basel) 2021; 14:ph14020126. [PMID: 33562742 PMCID: PMC7916085 DOI: 10.3390/ph14020126] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 01/30/2021] [Accepted: 02/01/2021] [Indexed: 02/07/2023] Open
Abstract
Osteoarthritis is a common, degenerative joint disease with significant socio-economic impact worldwide. There are currently no disease-modifying drugs available to treat the disease, making this an important area of pharmaceutical research. In this review, we assessed approaches being explored to directly inhibit metalloproteinase-mediated cartilage degradation and to counteract cartilage damage by promoting growth factor-driven repair. Metalloproteinase-blocking antibodies are discussed, along with recent clinical trials on FGF18 and Wnt pathway inhibitors. We also considered dendrimer-based approaches being developed to deliver and retain such therapeutics in the joint environment. These may reduce systemic side effects while improving local half-life and concentration. Development of such targeted anabolic therapies would be of great benefit in the osteoarthritis field.
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Yao B, Zhou Z, Zhang M, Leng X, Zhao D. Investigating the molecular control of deer antler extract on articular cartilage. J Orthop Surg Res 2021; 16:8. [PMID: 33407721 PMCID: PMC7788833 DOI: 10.1186/s13018-020-02148-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/02/2020] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Deer antler is considered as a precious traditional Chinese medicinal material and has been widely used to reinforce kidney's yang, nourish essence, and strengthen bone function. The most prominent bioactive components in deer antler are water-soluble proteins that play potential roles in bone formation and repair. The aim of this study was to explore the molecular control and therapeutic targets of deer antler extract (DAE) on articular cartilage. METHODS DAE was prepared as previously described. All rats were randomly divided into Blank group and DAE group (10 rats per group) after 7-day adaptive feeding. The rats in DAE group were orally administrated with DAE at a dose of 0.2 g/kg per day for 3 weeks, and the rats in Blank group were fed with drinking water. Total RNA was isolated from the articular cartilage of knee joints. RNA sequencing (RNA-seq) experiment combined with quantitative real-time polymerase chain reaction (qRT-PCR) verification assay was carried out to explore the molecular control and therapeutic targets of DAE on articular cartilage. RESULTS We demonstrated that DAE significantly increased the expression levels of functional genes involved in cartilage formation, growth, and repair and decreased the expression levels of susceptibility genes involved in the pathophysiology of osteoarthritis. CONCLUSIONS DAE might serve as a candidate supplement for maintaining cartilage homeostasis and preventing cartilage degeneration and inflammation. These effects were possibly achieved by accelerating the expression of functional genes involved in chondrocyte commitment, survival, proliferation, and differentiation and suppressing the expression of susceptibility genes involved in the pathophysiology of osteoarthritis. Thus, our findings will contribute towards deepening the knowledge about the molecular control and therapeutic targets of DAE on the treatment of cartilage-related diseases.
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Affiliation(s)
- Baojin Yao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117 China
| | - Zhenwei Zhou
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117 China
| | - Mei Zhang
- Innovation Practice Center, Changchun University of Chinese Medicine, Changchun, 130117 China
| | - Xiangyang Leng
- The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 130117 China
| | - Daqing Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117 China
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Abstract
PURPOSE OF REVIEW Current thinking in the study of posttraumatic osteoarthritis (PTOA) is overviewed: the osteoarthritis which follows acute joint injury. The review particularly highlights important publications in the last 18 months, also reflecting on key older literature, in terms of what have we have we learned and have yet to learn from PTOA, which can advance the osteoarthritis field as a whole. RECENT FINDINGS PTOA is a mechanically driven disease, giving insight into mechanical drivers for osteoarthritis. A mechanosensitive molecular tissue injury response (which includes activation of pain, degradative and also repair pathways) is triggered by acute joint injury and seen in osteoarthritis. Imaging features of PTOA are highly similar to osteoarthritis, arguing against it being a different phenotype. The inflammatory pathways activated by injury contribute to early joint symptoms. However, later structural changes appear to be dissociated from traditional measures of synovial inflammation. SUMMARY PTOA remains an important niche in which to understand processes underlying osteoarthritis and seek interventional targets. Whether PTOA has true molecular or clinical differences to osteoarthritis as a whole remains to be understood. This knowledge is important for a field where animal modelling of the disease relies heavily on the link between injury and osteoarthritis.
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Affiliation(s)
- Fiona E Watt
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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von Loga IS, Batchelor V, Driscoll C, Burleigh A, Chia SLL, Stott B, Miotla-Zarebska J, Riley D, Dell'Accio F, Vincent TL. Does Pain at an Earlier Stage of Chondropathy Protect Female Mice Against Structural Progression After Surgically Induced Osteoarthritis? Arthritis Rheumatol 2020; 72:2083-2093. [PMID: 32602242 DOI: 10.1002/art.41421] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 06/11/2020] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Female C57BL/6 mice exhibit less severe chondropathy than male mice. This study was undertaken to test the robustness of this observation and explore underlying mechanisms. METHODS Osteoarthritis was induced in male and female C57BL/6 or DBA/1 mice (n = 6-15 per group) by destabilization of the medial meniscus (DMM) or partial meniscectomy (PMX). Some mice were ovariectomized (OVX) (n = 30). In vivo repair after focal cartilage defect or joint immobilization (sciatic neurectomy) following DMM was assessed. Histologic analysis, evaluation of gene expression in whole knees, and behavioral analysis using Laboratory Animal Behavior Observation Registration and Analysis System (LABORAS) and Linton incapacitance testing (n = 7-10 mice per group) were performed. RESULTS Female mice displayed less severe chondropathy (20-75% reduction) across both strains and after both surgeries. Activity levels after PMX were similar for male and female mice. Some repair-associated genes were increased in female mouse joints after surgery, but no repair differences were evident in vivo. Despite reduced chondropathy, female mice developed pain-like behavior at the same time as male mice. At the time of established pain-like behavior (10 weeks after PMX), pain-associated genes were significantly up-regulated in female mice, including Gdnf (mean ± SEM fold change 2.54 ± 0.30), Nrtn (6.71 ± 1.24), Ntf3 (1.92 ± 0.27), and Ntf5 (2.89 ± 0.48) (P < 0.01, P < 0.01, P < 0.05, and P < 0.001, respectively, versus male mice). Inflammatory genes were not regulated in painful joints in mice of either sex. CONCLUSION We confirm strong structural joint protection in female mice that is not due to activity or intrinsic repair differences. Female mice develop pain at the same time as males, but induce a distinct set of neurotrophins. We speculate that heightened pain sensitivity in female mice protects the joint by preventing overuse.
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Affiliation(s)
| | - Vicky Batchelor
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Clare Driscoll
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Annika Burleigh
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Shi-Lu L Chia
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Bryony Stott
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | | | - David Riley
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | | | - Tonia L Vincent
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
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Blaker CL, Ashton DM, Doran N, Little CB, Clarke EC. Sex- and injury-based differences in knee biomechanics in mouse models of post-traumatic osteoarthritis. J Biomech 2020; 114:110152. [PMID: 33285491 DOI: 10.1016/j.jbiomech.2020.110152] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/21/2020] [Accepted: 11/23/2020] [Indexed: 01/14/2023]
Abstract
Sex and joint injury are risk factors implicated in the onset and progression of osteoarthritis (OA). In mouse models of post-traumatic OA (ptOA), the pathogenesis of disease is notably impacted by sex (often worse in males) and injury model (e.g. meniscal versus ligament injury). Increasing ptOA progression and severity is often associated with greater relative instability of the joint but few studies have directly quantified changes in joint mechanics after injury and compared outcomes across multiple models in both male and female mice. Passive anterior-posterior knee biomechanics were evaluated in 10-week-old, male and female C57BL/6J mice. PtOA injury models included destabilisation of the medial meniscus (DMM), anterior cruciate ligament transection (ACLT) or mechanical rupture (ACLR), and combined DMM and ACLT (DMM + ACLT). Sham operated and non-operated controls (NOC) were included for baseline comparisons. The test apparatus loaded hindlimbs at 60° flexion between ± 1 N at 0.5 mm/s (build specifications available for download: https://doi.org/10.17632/z754455x3c.1). Measures of joint laxity (range of motion, neutral zone) and stiffness were calculated. Joint laxity was comparable between male and female mice while joint stiffness was greater in females (P ≤ 0.002, correcting for body-mass and injury-model). Anterior-posterior joint mechanics were minimally altered by DMM but significantly affected by loss of the ACL (P < 0.001), with equivalent changes between ACL-injury models despite different injury mechanisms and adjacent meniscal damage. These findings suggest that despite the important role of joint injury; sex- and model-specific differences in ptOA progression and severity are not primarily driven by altered anterior-posterior knee biomechanics.
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Affiliation(s)
- Carina L Blaker
- Murray Maxwell Biomechanics Laboratory, Institute of Bone and Joint Research, Kolling Institute, Northern Sydney Local Health District, Faculty of Medicine and Health, University of Sydney, St. Leonards, New South Wales, Australia; Raymond Purves Bone and Joint Research Laboratories, Institute of Bone and Joint Research, Kolling Institute, Northern Sydney Local Health District, Faculty of Medicine and Health, University of Sydney, St. Leonards, New South Wales, Australia
| | - Dylan M Ashton
- Murray Maxwell Biomechanics Laboratory, Institute of Bone and Joint Research, Kolling Institute, Northern Sydney Local Health District, Faculty of Medicine and Health, University of Sydney, St. Leonards, New South Wales, Australia
| | - Nathan Doran
- Murray Maxwell Biomechanics Laboratory, Institute of Bone and Joint Research, Kolling Institute, Northern Sydney Local Health District, Faculty of Medicine and Health, University of Sydney, St. Leonards, New South Wales, Australia; School of Biomedical Engineering, University of New South Wales, Kensington, New South Wales, Australia
| | - Christopher B Little
- Raymond Purves Bone and Joint Research Laboratories, Institute of Bone and Joint Research, Kolling Institute, Northern Sydney Local Health District, Faculty of Medicine and Health, University of Sydney, St. Leonards, New South Wales, Australia
| | - Elizabeth C Clarke
- Murray Maxwell Biomechanics Laboratory, Institute of Bone and Joint Research, Kolling Institute, Northern Sydney Local Health District, Faculty of Medicine and Health, University of Sydney, St. Leonards, New South Wales, Australia.
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Zhu L, Donhou S, Burleigh A, Miotla Zarebska J, Curtinha M, Parisi I, Khan SN, Dell'Accio F, Chanalaris A, Vincent TL. TSG-6 Is Weakly Chondroprotective in Murine OA but Does not Account for FGF2-Mediated Joint Protection. ACR Open Rheumatol 2020; 2:605-615. [PMID: 33029956 PMCID: PMC7571392 DOI: 10.1002/acr2.11176] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 08/11/2020] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE Tumor necrosis factor α-stimulated gene 6 (TSG-6) is an anti-inflammatory protein highly expressed in osteoarthritis (OA), but its influence on the course of OA is unknown. METHODS Cartilage injury was assessed by murine hip avulsion or by recutting rested explants. Forty-two previously validated injury genes were quantified by real-time polymerase chain reaction in whole joints following destabilization of the medial meniscus (DMM) (6 hours and 7 days). Joint pathology was assessed at 8 and 12 weeks following DMM in 10-week-old male and female fibroblast growth factor 2 (FGF2)-/- , TSG-6-/- , TSG-6tg (overexpressing), FGF2-/- ;TSG-6tg (8 weeks only) mice, as well as strain-matched, wild-type controls. In vivo cartilage repair was assessed 8 weeks following focal cartilage injury in TSG-6tg and control mice. FGF2 release following cartilage injury was measured by enzyme-linked immunosorbent assay. RESULTS TSG-6 messenger RNA upregulation was strongly FGF2-dependent upon injury in vitro and in vivo. Fifteeen inflammatory genes were significantly increased in TSG-6-/- joints, including IL1α, Ccl2, and Adamts5 compared with wild type. Six genes were significantly suppressed in TSG-6-/- joints including Timp1, Inhibin βA, and podoplanin (known FGF2 target genes). FGF2 release upon cartilage injury was not influenced by levels of TSG-6. Cartilage degradation was significantly increased at 12 weeks post-DMM in male TSG-6-/- mice, with a nonsignificant 30% reduction in disease seen in TSG-6tg mice. No differences were observed in cartilage repair between genotypes. TSG-6 overexpression was unable to prevent accelerated OA in FGF2-/- mice. CONCLUSION TSG-6 influences early gene regulation in the destabilized joint and exerts a modest late chondroprotective effect. Although strongly FGF2 dependent, TSG-6 does not explain the strong chondroprotective effect of FGF2.
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Affiliation(s)
- Linyi Zhu
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
| | - Shannah Donhou
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
| | - Annika Burleigh
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
| | - Jadwiga Miotla Zarebska
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
| | - Marcia Curtinha
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
| | - Ida Parisi
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
| | - Sumayya Nafisa Khan
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
| | | | - Anastasios Chanalaris
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
| | - Tonia L Vincent
- Kennedy Institute of Rheumatology, Arthritis Research UK Centre for OA Pathogenesis, University of Oxford, UK
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Vincent TL. Of mice and men: converging on a common molecular understanding of osteoarthritis. THE LANCET. RHEUMATOLOGY 2020; 2:e633-e645. [PMID: 32989436 PMCID: PMC7511206 DOI: 10.1016/s2665-9913(20)30279-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Despite an increasing burden of osteoarthritis in developed societies, target discovery has been slow and there are currently no approved disease-modifying osteoarthritis drugs. This lack of progress is due in part to a series of misconceptions over the years: that osteoarthritis is an inevitable consequence of ageing, that damaged articular cartilage cannot heal itself, and that osteoarthritis is driven by synovial inflammation similar to that seen in rheumatoid arthritis. Molecular interrogation of disease through ex-vivo tissue analysis, in-vitro studies, and preclinical models have radically reshaped the knowledge landscape. Inflammation in osteoarthritis appears to be distinct from that seen in rheumatoid arthritis. Recent randomised controlled trials, using treatments repurposed from rheumatoid arthritis, have largely been unsuccessful. Genome-wide studies point to defects in repair pathways, which accords well with recent promise using growth factor therapies or Wnt pathway antagonism. Nerve growth factor has emerged as a robust target in osteoarthritis pain in phase 2-3 trials. These studies, both positive and negative, align well with those in preclinical surgical models of osteoarthritis, indicating that pathogenic mechanisms identified in mice can lead researchers to valid human targets. Several novel candidate pathways are emerging from preclinical studies that offer hope of future translational impact. Enhancing trust between industry, basic, and clinical scientists will optimise our collective chance of success.
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Affiliation(s)
- Tonia L Vincent
- Centre for Osteoarthritis Pathogenesis, Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
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Yang Z, Ni J, Kuang L, Gao Y, Tao S. Identification of genes and pathways associated with subchondral bone in osteoarthritis via bioinformatic analysis. Medicine (Baltimore) 2020; 99:e22142. [PMID: 32925767 PMCID: PMC7489699 DOI: 10.1097/md.0000000000022142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 03/15/2020] [Accepted: 08/09/2020] [Indexed: 11/30/2022] Open
Abstract
Osteoarthritis (OA) is a high prevalent musculoskeletal problem, which can cause severe pain, constitute a huge social and economic burden, and seriously damage the quality of life. This study was intended to identify genetic characteristics of subchondral bone in patients with OA and to elucidate the potential molecular mechanisms involved. Data of gene expression profiles (GSE51588), which contained 40 OA samples and 10 normal samples, was obtained from the Gene Expression Omnibus (GEO). The raw data were integrated to obtain differentially expressed genes (DEGs) and were further analyzed with bioinformatic analysis. The protein-protein interaction (PPI) networks were built and analyzed via Search Tool for the Retrieval of Interacting Genes (STRING). The significant modules and hub genes were identified via Cytoscape. Moreover, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis were performed. Totally 235 DEGs were differentially expressed in the subchondral bone from OA patients compared with those of normal individuals, of which 78 were upregulated and 157 were downregulated. Eight hub genes were identified, including DEFA4, ARG1, LTF, RETN, PGLYRP1, OLFM4, ORM1, and BPI. The enrichment analyses of the DEGs and significant modules indicated that DEGs were mainly involved in inflammatory response, extracellular space, RAGE receptor binding, and amoebiasis pathway. The present study provides a novel and in-depth understanding of pathogenesis of the OA subchondral bone at molecular level. DEFA4, ARG1, LTF, RETN, PGLYRP1, OLFM4, ORM1, and BPI may be the new candidate targets for diagnosis and therapies on patients with OA in the future.
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Affiliation(s)
- Zhanyu Yang
- Department of Orthopaedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University
- Hunan Provincial Emergency Center
| | - Jiangdong Ni
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan
| | - Letian Kuang
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan
| | - Yongquan Gao
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan
| | - Shibin Tao
- Department of Orthopaedics, Qinghai University Affiliated Hospital, Xining, Qinghai, P.R. China
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Mechanoflammation in osteoarthritis pathogenesis. Semin Arthritis Rheum 2020; 49:S36-S38. [PMID: 31779850 DOI: 10.1016/j.semarthrit.2019.09.018] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 11/22/2022]
Abstract
Mechanical injury is the most important risk factor in osteoarthritis (OA) development. Although once considered a passive disease of mechanical attrition, injury drives active mechanosensitive intracellular signalling which affects the structural and symptomatic course of disease. Mechanosensitive signalling in cartilage has been elucidated over the years and two principal responses emerge: those that cause the release of growth factors from the matrix and which stimulate repair, and those that drive inflammatory signalling, a process that we have termed "mechanoflammation". The up-stream activator of mechanoflammation remains unknown, but it results in rapid activation of NFkB and the inflammatory mitogen activated protein (MAP) kinases and this controls the bioavailability of aggrecanase and regulation of nerve growth factor (NGF), causing pain. The precise relationship between mechanoflammation and cartilage repair is currently unclear but it is likely that chronic mechanoflammation will contribute to disease by also suppressing intrinisic tissue repair.
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48
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Kruppel-like factor 4 upregulates matrix metalloproteinase 13 expression in chondrocytes via mRNA stabilization. Cell Tissue Res 2020; 382:307-319. [PMID: 32556726 DOI: 10.1007/s00441-020-03228-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 04/29/2020] [Indexed: 10/24/2022]
Abstract
Matrix metalloproteinase 13 (MMP13) is indispensable for normal skeletal development and is also a principal proteinase responsible for articular joint pathologies. MMP13 mRNA level needs to be tightly regulated in both positive and negative manners to achieve normal development and also to prevent joint destruction. We showed previously that Kruppel-like factor 4 (KLF4) strongly induces the expression of members of the MMP family of genes including that for MMP13 in cultured chondrocytes. Through expression-based screening of approximately 400 compounds, we identified several that efficiently downregulated MMP13 gene expression induced by KLF4. Compounds grouped as topoisomerase inhibitors (transcriptional inhibitors) downregulated MMP13 expression levels, which proved the validity of our screening method. In this screening, trichostatin A (TSA) was identified as one of the most potent repressors. Mechanistically, increased MMP13 mRNA levels induced by KLF4 were not mainly caused by increased rates of RNA polymerase II-mediated MMP13 transcription, but arose from escaping mRNA decay. TSA treatment almost completely blunted the effect of KLF4. Importantly, KLF4 was detected in chondrocytes at the joint destruction sites in a rodent model of osteoarthritis. Our results partially explain how KLF4 regulates numerous proteinase gene expressions simultaneously in chondrocytes. Also, these observations suggest that modulation of KLF4 activity or expression could be a novel therapeutic target for osteoarthritis.
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Lu K, Yang K, Niyongabo E, Shu Z, Wang J, Chang K, Zou Q, Jiang J, Jia C, Liu B, Zhou X. Integrated network analysis of symptom clusters across disease conditions. J Biomed Inform 2020; 107:103482. [PMID: 32535270 DOI: 10.1016/j.jbi.2020.103482] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 05/18/2020] [Accepted: 06/08/2020] [Indexed: 10/24/2022]
Abstract
Identifying the symptom clusters (two or more related symptoms) with shared underlying molecular mechanisms has been a vital analysis task to promote the symptom science and precision health. Related studies have applied the clustering algorithms (e.g. k-means, latent class model) to detect the symptom clusters mostly from various kinds of clinical data. In addition, they focused on identifying the symptom clusters (SCs) for a specific disease, which also mainly concerned with the clinical regularities for symptom management. Here, we utilized a network-based clustering algorithm (i.e., BigCLAM) to obtain 208 typical SCs across disease conditions on a large-scale symptom network derived from integrated high-quality disease-symptom associations. Furthermore, we evaluated the underlying shared molecular mechanisms for SCs, i.e., shared genes, protein-protein interaction (PPI) and gene functional annotations using integrated networks and similarity measures. We found that the symptoms in the same SCs tend to share a higher degree of genes, PPIs and have higher functional homogeneities. In addition, we found that most SCs have related symptoms with shared underlying molecular mechanisms (e.g. enriched pathways) across different disease conditions. Our work demonstrated that the integrated network analysis method could be used for identifying robust SCs and investigate the molecular mechanisms of these SCs, which would be valuable for symptom science and precision health.
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Affiliation(s)
- Kezhi Lu
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Kuo Yang
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Edouard Niyongabo
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Zixin Shu
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Jingjing Wang
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Kai Chang
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Qunsheng Zou
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Jiyue Jiang
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Caiyan Jia
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
| | - Baoyan Liu
- Data Center of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Xuezhong Zhou
- Institute of Medical Intelligence, School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China; Data Center of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
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Watt FE, Hamid B, Garriga C, Judge A, Hrusecka R, Custers RJH, Jansen MP, Lafeber FP, Mastbergen SC, Vincent TL. The molecular profile of synovial fluid changes upon joint distraction and is associated with clinical response in knee osteoarthritis. Osteoarthritis Cartilage 2020; 28:324-333. [PMID: 31904489 PMCID: PMC7054834 DOI: 10.1016/j.joca.2019.12.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 12/14/2019] [Accepted: 12/22/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Surgical knee joint distraction (KJD) leads to clinical improvement in knee osteoarthritis (OA) and also apparent cartilage regeneration by magnetic resonance imaging. We investigated if alteration of the joint's mechanical environment during the 6 week period of KJD was associated with a molecular response in synovial fluid, and if any change was associated with clinical response. METHOD 20 individuals undergoing KJD for symptomatic radiographic knee OA had SF sampled at baseline, midpoint and endpoint of distraction (6 weeks). SF supernatants were measured by immunoassay for 10 predefined mechanosensitive molecules identified in our previous pre-clinical studies. The composite Knee injury and OA Outcome Score-4 (KOOS4) was collected at baseline, 3, 6 and 12 months. RESULTS 13/20 (65%) were male with mean age 54°±°5yrs. All had Kellgren-Lawrence grade ≥2 knee OA. 6/10 analytes showed statistically significant change in SF over the 6 weeks distraction (activin A; TGFβ-1; MCP-1; IL-6; FGF-2; LTBP2), P < 0.05. Of these, all but activin A increased. Those achieving the minimum clinically important difference of 10 points for KOOS4 over 6 months showed greater increases in FGF-2 and TGFβ-1 than non-responders. An increase in IL-8 during the 6 weeks of KJD was associated with significantly greater improvement in KOOS4 over 12 months. CONCLUSION Detectable, significant molecular changes are observed in SF following KJD, that are remarkably consistent between individuals. Preliminary findings appear to suggest that increases in some molecules are associated with clinically meaningful responses. Joint distraction may provide a potential opportunity in the future to define regenerative biomarker(s) and identify pathways that drive intrinsic cartilage repair.
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Affiliation(s)
- F E Watt
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, Roosevelt Drive, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.
| | - B Hamid
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.
| | - C Garriga
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.
| | - A Judge
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK; Musculoskeletal Research Unit, University of Bristol, UK; National Institute for Health Research Bristol Biomedical Research Centre (NIHR Bristol BRC), University Hospitals Bristol NHS Foundation Trust, UK; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.
| | - R Hrusecka
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.
| | - R J H Custers
- Department of Orthopaedic Surgery, University Medical Center Utrecht, the Netherlands.
| | - M P Jansen
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, the Netherlands.
| | - F P Lafeber
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, the Netherlands.
| | - S C Mastbergen
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, the Netherlands.
| | - T L Vincent
- Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK.
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