|
1
|
Manouchehri JM, Datta J, Marcho LM, Stover D, Ganju RK, Ramaswamy B, Carson WE, Mittra A, Zhang X, Schnell PM, Yue Y, Rubinstein MP, Cherian MA. Sulfatase 2 inhibition sensitizes triple-negative breast cancer cells to paclitaxel through augmentation of extracellular ATP. Cancer Biol Ther 2025; 26:2483989. [PMID: 40140347 PMCID: PMC11951697 DOI: 10.1080/15384047.2025.2483989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 01/09/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
The highest incidence and cancer-related mortality rate among women worldwide is due to breast cancer. Triple-negative breast cancers (TNBC) are associated with more inferior outcomes than other breast cancers because of their progressive nature and the deficit in available therapies. Therefore, there is a need for new therapeutic approaches. Our lab determined that chemotherapy induces the release of extracellular adenosine triphosphate (eATP), and, hence, augments TNBC cells' response to chemotherapy. Despite this, eATP concentrations are restricted by a variety of extracellular ATPases. We propose that, as an ATPase inhibitor, heparan sulfate (HS) would augment eATP concentrations and TNBC vulnerability induced by chemotherapy. Sulfatase 2 (SULF2) removes sulfate from HS, the functional group essential for ATPase inhibition. Consequently, we propose that TNBC cell death and eATP release induced by chemotherapy would be intensified by SULF2 inhibitors. We examined eATP and cell viability in paclitaxel-treated TNBC and nontumorigenic immortal mammary epithelial MCF-10A cells in the presence of OKN-007, a selective SULF2 inhibitor, and/or heparan sodium sulfate. Furthermore, sulfatase 1 (SULF1) and SULF2 protein expressions were ascertained. We found that the expression of SULF2 was greater in TNBC cell lines when compared to MCF-10A cells. The release of eATP and loss of TNBC cell viability induced by chemotherapy was enhanced by OKN-007. The co-treatment of chemotherapy and OKN-007 also attenuated cancer-initiating cells. This data implies that the combination of SULF2 inhibitors with chemotherapy augments eATP and decreases cell viability of TNBC greater than chemotherapy alone.
Collapse
Affiliation(s)
| | - Jharna Datta
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Lynn M. Marcho
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Daniel Stover
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Ramesh K. Ganju
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | | | - William E. Carson
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Arjun Mittra
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Xiaoli Zhang
- College of Nursing, University of South Florida, Tampa, FL, USA
| | | | - Yu Yue
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Mark P. Rubinstein
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Mathew A. Cherian
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| |
Collapse
|
|
2
|
Ito K, Nishida Y, Ikuta K, Urakawa H, Sakai T, Koike H, Nishida K, Imagama S. Clinical factors associated with valgus knee deformities in patients with multiple osteochondromas. Medicine (Baltimore) 2025; 104:e42359. [PMID: 40355239 PMCID: PMC12073857 DOI: 10.1097/md.0000000000042359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 04/18/2025] [Indexed: 05/14/2025] Open
Abstract
Multiple osteochondromas (MO) occur in approximately 1 in 50,000 people/yr. One in 3 patients with MO will develop valgus knee deformity (VKD), but the predictive factors for VKD are unclear. The purpose of this study was to examine the factors associated with VKD in patients with MO. From January 2003 to December 2018, 64 patients with MO visited the Nagoya University Hospital for the 1st time. Thirty-three patients with 66 limbs were sequentially included in the study after excluding 12 patients with a history of lower extremity surgery, 15 patients whose knee X-rays were unavailable, and 4 patients whose age at the last examination was <7 years. Limbs with femorotibial angle (FTA) ≥ 175° were defined as the normal group (Group N) and limbs with FTA < 175° as the valgus group (Group V), and clinical factors collected retrospectively from the medical records were compared between the 2 groups. The initial and final X-rays were compared in a subgroup analysis of 8 patients whose initial examination was <10 years old and who were followed for more than 5 years. Twenty-four males and 9 females with a median age of 17 years at the last X-rays were included in the study. The mean follow-up period was 43 ± 53 months, and the median FTA was 174.5°. Group N consisted of 32 limbs and Group V consisted of 34 limbs. Multivariate analysis was performed using the 5 factors with P-values <.15 in the univariate analysis of comparison between the 2 groups, and only medial proximal tibial angle showed significant differences (P < .001). In the subgroup analysis, multivariate analysis showed that the femoral neck-shaft angle showed significant differences between the 2 groups at the initial evaluation (P < .001). Our study suggests that medial proximal tibial angle is associated with VKD in patients with MO. Small neck-shaft angle was significantly associated with VKD, even before it became obvious. In order to study how VKD is formed, imaging of the hip and ankle joints and X-rays of the entire lower extremity should be performed in more cases.
Collapse
Affiliation(s)
- Kan Ito
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Yoshihiro Nishida
- Department of Rehabilitation, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Kunihiro Ikuta
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Hiroshi Urakawa
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Tomohisa Sakai
- Rare Cancer Center, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Hiroshi Koike
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Kazuki Nishida
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Shiro Imagama
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| |
Collapse
|
|
3
|
Alharbi H, Horikoshi S, Jenkins SM, Scaglia F, Lam C, Morava E, Larson A, Edmondson AC. Causes of mortality in the congenital disorders of glycosylation. Mol Genet Metab 2025; 144:109052. [PMID: 39923392 PMCID: PMC11892340 DOI: 10.1016/j.ymgme.2025.109052] [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: 12/05/2024] [Revised: 01/31/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
Congenital Disorders of Glycosylation (CDG) are a group of some 200 genetic disorders with PMM2-CDG being the most common disease. These disorders individually remain rare with poorly understood natural history (NH) and causes of mortality. We established a NH study for CDG and collected both prospective and retrospective data on CDG outcomes. In the current data set analysis on deceased patients, we describe the clinical phenotype and causes of death for thirty-seven individuals with various genetic causes of CDG. About a third of this cohort were affected with PMM2-CDG. All of the patients presented with multisystem features with involvement of the neurological system. The majority of patients involved in this study died during the first three years of life, and only four patients lived beyond ten years. The cause of death was unavailable for two patients, and about a third died secondary to cardiopulmonary failure. Progression of neurological involvement, sepsis and respiratory infection were also among the reported causes. Pericardial effusion was the primary cause of death for three infants affected with PMM2-CDG. This study emphasizes the importance of diagnosis and supportive care following the published monitoring and management guidelines for affected patients with CDG to optimize their health and development in the early stages of the disease.
Collapse
Affiliation(s)
- Hana Alharbi
- Department of Pediatrics, Faculty of Medicine, University of Tabuk, Saudi Arabia; Department of Medical Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia
| | - Seishu Horikoshi
- Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
| | | | - Fernando Scaglia
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Hong Kong SAR, China
| | - Christina Lam
- Norcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA; Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - Eva Morava
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Austin Larson
- Department of Pediatrics, Section of Genetics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Andrew C Edmondson
- Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, PA, USA.
| |
Collapse
|
|
4
|
Borovikov A, Marakhonov A, Murtazina A, Davydenko K, Filatova A, Galeeva N, Kadnikova V, Ogorodova N, Gorodilova D, Kanivets I, Pyankov D, Zherdev K, Petel’guzov A, Zubkov P, Polyakov A, Shchagina O, Skoblov M. Cases report: Mosaic structural variants of the EXT1 gene in previously genetically unconfirmed multiple osteochondromas. Front Genet 2024; 15:1435493. [PMID: 39192890 PMCID: PMC11347319 DOI: 10.3389/fgene.2024.1435493] [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: 05/20/2024] [Accepted: 07/26/2024] [Indexed: 08/29/2024] Open
Abstract
Multiple osteochondromas (MO) is a rare autosomal dominant skeletal disorder characterized by the development of multiple benign tumors known as osteochondromas. The condition is predominantly caused by loss-of-function variants in the EXT1 or EXT2 genes, facilitating relatively precise clinical diagnosis through established diagnostic criteria. Despite this, a notable percentage of MO cases (10%-20%) remains unresolved after sequencing coding regions and copy number analysis of both genes. In our study, we identified mosaic structural variants in two patients who initially yielded negative results on standard genetic analysis for MO. Specifically, mosaic deletions affecting exons 8-11 and exons 2-11 in the EXT1 gene were detected. RNA analysis was performed in one case, while both cases underwent genome sequencing. To date, only six mosaic copy number variations have been reported in association with MO, representing a minority among known variants in both genes. Our report provides a detailed analysis of these findings, highlighting the significance of advanced genetic testing techniques in detecting mosaic variants in the EXT1/2 genes.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | - Ilya Kanivets
- Genomed, Moscow, Russia
- Federal State Budgetary Educational Institution, Further Professional Education, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | | | - Konstantin Zherdev
- National Medical Research Center of Children’s Health, Moscow, Russia
- Department of Pediatric Surgery and Urology-Andrology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Pavel Zubkov
- National Medical Research Center of Children’s Health, Moscow, Russia
| | | | | | | |
Collapse
|
|
5
|
Garcia SA, Wilson K, Tang N, Tian H, Oichi T, Gunawardena AT, Chorny M, Alferiev IS, Herzenberg JE, Ng VY, Iwamoto M, Enomoto-Iwamoto M. Analysis of the Actions of RARγ Agonists on Growing Osteochondromas in a Mouse Model. Int J Mol Sci 2024; 25:7610. [PMID: 39062860 PMCID: PMC11277217 DOI: 10.3390/ijms25147610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 06/28/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma masses, and the findings from preclinical investigations are the effects of drugs on the initial formation of osteochondromas. Systemic administration of palovarotene, with increased doses (from 1.76 to 4.0 mg/kg) over time, fully inhibited tumor growth, keeping the tumor size (0.31 ± 0.049 mm3) similar to the initial size (0.27 ± 0.031 mm3, p = 0.66) while the control group tumor grew (1.03 ± 0.23 mm3, p = 0.023 to the drug-treated group). Nanoparticle (NP)-based local delivery of the RARγ agonist also inhibited the growth of osteochondromas at an early stage (Control: 0.52 ± 0.11 mm3; NP: 0.26 ± 0.10, p = 0.008). Transcriptome analysis revealed that the osteoarthritis pathway was activated in cultured chondrocytes treated with palovarotene (Z-score = 2.29), with the upregulation of matrix catabolic genes and the downregulation of matrix anabolic genes, consistent with the histology of palovarotene-treated osteochondromas. A reporter assay performed in cultured chondrocytes demonstrated that the Stat3 pathway, but not the Stat1/2 pathway, was stimulated by RARγ agonists. The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene.
Collapse
Affiliation(s)
- Sonia A. Garcia
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.A.G.); (K.W.); (N.T.); (H.T.); (T.O.); (V.Y.N.); (M.I.)
| | - Kimberly Wilson
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.A.G.); (K.W.); (N.T.); (H.T.); (T.O.); (V.Y.N.); (M.I.)
| | - Ningfeng Tang
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.A.G.); (K.W.); (N.T.); (H.T.); (T.O.); (V.Y.N.); (M.I.)
| | - Hongying Tian
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.A.G.); (K.W.); (N.T.); (H.T.); (T.O.); (V.Y.N.); (M.I.)
| | - Takeshi Oichi
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.A.G.); (K.W.); (N.T.); (H.T.); (T.O.); (V.Y.N.); (M.I.)
- Department of Orthopedics, Teikyo University School of Medicine, Tokyo 1738608, Japan
| | - Aruni T. Gunawardena
- Department of Biomechanics, Northeast College of Health Sciences, Seneca Falls, NY 13148, USA;
| | - Michael Chorny
- Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (M.C.); (I.S.A.)
| | - Ivan S. Alferiev
- Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; (M.C.); (I.S.A.)
| | - John E. Herzenberg
- International Center for Limb Lengthening, Rubin Institute for Advanced Orthopedics, Sinai Hospital of Baltimore, Baltimore, MD 21215, USA;
| | - Vincent Y. Ng
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.A.G.); (K.W.); (N.T.); (H.T.); (T.O.); (V.Y.N.); (M.I.)
| | - Masahiro Iwamoto
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.A.G.); (K.W.); (N.T.); (H.T.); (T.O.); (V.Y.N.); (M.I.)
| | - Motomi Enomoto-Iwamoto
- Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (S.A.G.); (K.W.); (N.T.); (H.T.); (T.O.); (V.Y.N.); (M.I.)
| |
Collapse
|
|
6
|
Borovikov A, Galeeva N, Marakhonov A, Murtazina A, Kadnikova V, Davydenko K, Orlova A, Sparber P, Markova T, Orlova M, Osipova D, Nagornova T, Semenova N, Levchenko O, Filatova A, Sharova M, Vasiluev P, Kanivets I, Pyankov D, Sharkov A, Udalova V, Kenis V, Nikitina N, Sumina M, Zherdev K, Petel'guzov A, Chelpachenko O, Zubkov P, Dan I, Snetkov A, Akinshina A, Buklemishev Y, Ryzhkova O, Tabakov V, Zakharova E, Korostelev S, Zinchenko R, Skoblov M, Polyakov A, Dadali E, Kutsev S, Shchagina O. The Missing Piece of the Puzzle: Unveiling the Role of PTPN11 Gene in Multiple Osteochondromas in a Large Cohort Study. Hum Mutat 2024; 2024:8849348. [PMID: 40225915 PMCID: PMC11918999 DOI: 10.1155/2024/8849348] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 11/22/2023] [Accepted: 01/10/2024] [Indexed: 04/15/2025]
Abstract
This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying multiple benign bone tumors known as osteochondromas (OCs) through imaging studies and physical examinations. However, cases with both OCs and enchondromas (ECs) may indicate the more rare condition metachondromatosis (MC), which is assumed to be distinct disease. Previous cohort studies of MO found heterozygous loss-of-function (LoF) variants only in the EXT1 or EXT2 genes, with DNA diagnostic yield ranging from 78 to 95%. The PTPN11 gene, which is causative for MC, was not previously investigated as a gene candidate for MO. In this study, we detected a total of 177 unique single nucleotide and copy number variants in three genes across 220 probands, consisting of 80 previously reported and 97 novel variants. Specifically, we identified five cases with OCs and no ECs as well as four cases with MC carrying LoF variants in the PTPN11 gene and two additional cases with ECs harboring variants in the EXT1/2 genes. These findings suggest a potential overlap between the MO and MC both phenotypically and genetically. These findings highlight the importance of expanding genetic testing beyond the EXT1 and EXT2 genes in MO cases, as other genes such as PTPN11 may also be causative. This can improve the accuracy of diagnosis and treatment for individuals with MO and MC. It is essential to determine whether MO and MC represent distinct diseases or if they encompass a broader clinical spectrum.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Anna Orlova
- Research Centre for Medical Genetics, Moscow, Russia
| | - Peter Sparber
- Research Centre for Medical Genetics, Moscow, Russia
| | | | - Maria Orlova
- Research Centre for Medical Genetics, Moscow, Russia
| | - Darya Osipova
- Research Centre for Medical Genetics, Moscow, Russia
| | | | | | | | | | | | | | - Ilya Kanivets
- Genomed, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
| | | | - Artem Sharkov
- Genomed, Moscow, Russia
- Veltischev Research and Clinical Institute of Pediatrics and Pediatric Surgery of the Pirogov Russian National Research Medical University, Moscow, Russia
| | | | - Vladimir Kenis
- The Turner Scientific Research Institute for Children's Orthopedics, Saint Petersburg, Russia
| | - Natalia Nikitina
- State Healthcare Institution of Sverdlovsk Region “Clinical and Diagnostic Center “Mother's and Child Health Protection”, Ekaterinburg, Russia
| | - Maria Sumina
- State Healthcare Institution of Sverdlovsk Region “Clinical and Diagnostic Center “Mother's and Child Health Protection”, Ekaterinburg, Russia
| | - Konstantin Zherdev
- National Medical Research Center of Children's Health, Moscow, Russia
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Oleg Chelpachenko
- National Medical Research Center of Children's Health, Moscow, Russia
| | - Pavel Zubkov
- National Medical Research Center of Children's Health, Moscow, Russia
| | - Ivan Dan
- National Medical Research Center of Traumatology and Orthopedics Named after N.N. Priorov, Moscow, Russia
| | - Andrey Snetkov
- National Medical Research Center of Traumatology and Orthopedics Named after N.N. Priorov, Moscow, Russia
| | - Alexandra Akinshina
- National Medical Research Center of Traumatology and Orthopedics Named after N.N. Priorov, Moscow, Russia
| | - Yury Buklemishev
- National Medical Research Center of Traumatology and Orthopedics Named after N.N. Priorov, Moscow, Russia
| | | | | | | | - Sergey Korostelev
- Genomed, Moscow, Russia
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | | | | | | | - Elena Dadali
- Research Centre for Medical Genetics, Moscow, Russia
| | - Sergey Kutsev
- Research Centre for Medical Genetics, Moscow, Russia
| | | |
Collapse
|
|
7
|
Katsuki R, Oshiro H, Aoki Y, Mizuta K, Tome Y, Nishida K. Rare coexistence of multiple osteochondromas and solitary osteoid osteoma: A case report. Mol Clin Oncol 2024; 20:13. [PMID: 38213658 PMCID: PMC10777465 DOI: 10.3892/mco.2023.2711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 12/04/2023] [Indexed: 01/13/2024] Open
Abstract
Multiple osteochondromas (MOs) are inherited in an autosomal-dominant manner, with a penetrance of ~96 and 100% in female and male patients, respectively. Osteochondromas primarily involve the metaphyses and diaphyses of long bones, including the ribs. Osteoid osteomas account for ~3 and 11% of all bone tumors and benign bone tumors, respectively. Furthermore,1 the male-to-female ratio is 2-3:1, and they generally occur in the long bones of the lower extremities, with the femoral neck being the most frequent site. The present study describes the case of a 16-year-old male patient with a bony mass around the left knee joint and pain in the left calf. Radiography revealed MOs in the upper and lower extremities, while computed tomography showed a nidus in the cortex of the tibial shaft. The patient's family history included the presence of MOs, and the patient was diagnosed with MOs and a solitary osteoid osteoma. Surgical excision of the osteochondroma and curettage of the osteoid osteoma in the proximal tibia and tibial shaft, respectively, were performed simultaneously. Postoperative pathological examination revealed osteochondroma and osteoid osteoma. Furthermore, the pain resolved, and no recurrence was observed 7 months post-operation. To the best of our knowledge, no reports exist on coexisting MOs and osteoid osteoma; therefore, the present study describes the first case of such a condition. Marginal excision for osteochondroma and curettage for osteoid osteoma effectively improved the symptoms.
Collapse
Affiliation(s)
- Ryo Katsuki
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Hiromichi Oshiro
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Yusuke Aoki
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Kohei Mizuta
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Yasunori Tome
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| | - Kotaro Nishida
- Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan
| |
Collapse
|
|
8
|
Ye T, Jiang M, Zeng X, Zong D, Du Y, Li X, Huang B, Tang X. Clinical significance of exostosin 1 in confirmed and suspected lupus membranous nephropathy. Lupus Sci Med 2023; 10:e001051. [PMID: 38154829 PMCID: PMC10759090 DOI: 10.1136/lupus-2023-001051] [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: 09/14/2023] [Accepted: 12/11/2023] [Indexed: 12/30/2023]
Abstract
OBJECTIVE This study aimed to investigate the clinical significance of exostosin 1 (EXT1) in confirmed and suspected lupus membranous nephropathy (LMN). METHODS EXT1 was detected in 67 renal tissues of M-type phospholipase A2 receptor (PLA2R)-negative and ANA-positive membranous nephropathy by immunohistochemistry, and cases were divided into confirmed LMN and suspected LMN. The clinicopathological data were compared among the above groups, as well as EXT1-positive group and EXT1-negative group. RESULTS Twenty-two cases (73.3%) of confirmed LMN and six cases (16.2%) of suspected LMN exhibited EXT1 expression on the glomerular basement membrane and/or mesangium area, showing a significant difference (p<0.001). Concurrently, lupus nephritis (LN) of pure class V demonstrated a lower frequency of EXT1 positivity compared with mixed class V LN in the confirmed LMN group (31.8% vs 68.2%, p=0.007). EXT1-positive patients in the confirmed and suspected LMN group showed significant differences in some clinicopathological data comparing with EXT1-negative patients (p<0.05). Follow-up data revealed that a greater proportion of patients in the EXT1-positive group achieved complete remission post-treatment (p<0.05). Cox regression analysis showed that EXT1 positivity was significantly correlated with complete remission across the entire study cohort (HR 5.647; 95% CI, 1.323 to 12.048; p=0.019). Kaplan-Meier analysis indicated that the EXT1-positive group had a higher rate of accumulated nephrotic remission compared with the EXT1-negative group in the whole study cohort (p=0.028). CONCLUSIONS The EXT1-positive group exhibited a higher active index and a more favourable renal outcome than the EXT1-negative group. It would be better to recognise suspected LMN with EXT1 positivity as a potential autoimmune disease and maintain close follow-up due to its similarities with confirmed LMN.
Collapse
Affiliation(s)
- Tian Ye
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Mengya Jiang
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xueyan Zeng
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Dan Zong
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yuanyuan Du
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xiaohong Li
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Biao Huang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China
| | - Xuanli Tang
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| |
Collapse
|
|
9
|
Yang S, He Z, Wu T, Wang S, Dai H. Glycobiology in osteoclast differentiation and function. Bone Res 2023; 11:55. [PMID: 37884496 PMCID: PMC10603120 DOI: 10.1038/s41413-023-00293-6] [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: 02/11/2023] [Revised: 08/20/2023] [Accepted: 09/07/2023] [Indexed: 10/28/2023] Open
Abstract
Glycans, either alone or in complex with glycan-binding proteins, are essential structures that can regulate cell biology by mediating protein stability or receptor dimerization under physiological and pathological conditions. Certain glycans are ligands for lectins, which are carbohydrate-specific receptors. Bone is a complex tissue that provides mechanical support for muscles and joints, and the regulation of bone mass in mammals is governed by complex interplay between bone-forming cells, called osteoblasts, and bone-resorbing cells, called osteoclasts. Bone erosion occurs when bone resorption notably exceeds bone formation. Osteoclasts may be activated during cancer, leading to a range of symptoms, including bone pain, fracture, and spinal cord compression. Our understanding of the role of protein glycosylation in cells and tissues involved in osteoclastogenesis suggests that glycosylation-based treatments can be used in the management of diseases. The aims of this review are to clarify the process of bone resorption and investigate the signaling pathways mediated by glycosylation and their roles in osteoclast biology. Moreover, we aim to outline how the lessons learned about these approaches are paving the way for future glycobiology-focused therapeutics.
Collapse
Affiliation(s)
- Shufa Yang
- Prenatal Diagnostic Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China
| | - Ziyi He
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China
| | - Tuo Wu
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China
| | - Shunlei Wang
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China
| | - Hui Dai
- Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China.
| |
Collapse
|
|
10
|
Manouchehri JM, Marcho L, Cherian MA. Sulfatase 2 Inhibition Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy Through Augmentation of Extracellular ATP. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.15.557965. [PMID: 37745565 PMCID: PMC10516004 DOI: 10.1101/2023.09.15.557965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Background Breast cancer is the leading cause of cancer-related death among women worldwide. Patients diagnosed with triple-negative breast cancer (TNBC) have limited therapeutic options that produce durable responses. Hence, a diagnosis of TNBC is associated with a poor prognosis compared to other types of breast cancer. As a result, there is a critical need for novel therapies that can deepen and prolong responses.We previously found that chemotherapy causes the release of extracellular adenosine triphosphate (eATP). Augmenting eATP release can boost the response of TNBC cells to chemotherapy and cause increased cell death. However, eATP concentrations are limited by several families of extracellular ATPases, which complicates the design of compounds that attenuate eATP degradation.In this study, we hypothesized that heparan sulfate (HS) would inhibit extracellular ATPases and accentuate chemotherapy-induced cytotoxicity in TNBC by augmenting eATP. HS can be desulfated by sulfatase 1 and 2; sulfatase 2 is consistently highly expressed in a variety of cancers including breast cancer, whereas sulfatase 1 is not. We hypothesized that the sulfatase 2 inhibitor OKN-007 would exacerbate chemotherapy-induced eATP release and TNBC cell death. Methods TNBC cell lines and nontumorigenic immortal mammary epithelial cells were treated with paclitaxel in the presence of heparan sodium sulfate and/or OKN-007; eATP content and cell viability were evaluated. In addition, protein and cell surface expression of sulfatases 1 and 2 were determined in all examined cell lines via ELISA, Western blot, and flow cytometry analyses. Results Sulfatase 2 was highly expressed in TNBC cell lines and human breast cancer samples but not in immortal mammary epithelial cells and much less so in normal human breast tissue and ductal carcinoma in situ samples. OKN-007 exacerbated chemotherapy-induced eATP release and chemotherapy-induced TNBC cell death. When combined with chemotherapy, OKN-007 attenuated cells with a cancer-initiating cell phenotype. Conclusions These results suggest that sulfatase 2 inhibitors in combination with chemotherapy attenuate the viability of TNBC cells more than chemotherapy alone by exacerbating eATP release. These effects, as well as their capacity to attenuate the cancer-initiating cell fraction, may translate into combination therapies for TNBC that induce deeper and more durable responses.
Collapse
|
|
11
|
Cao S, Zeng JF, Xiao S, Dong ZG, Xu ZL, Liu H, Li X, Fang K, Wen J, Zeng M, Tang ZW, Li B, Gong HL, Li FL. Modified ulnar lengthening for correction of the Masada type 2 forearm deformity in hereditary multiple exostosis. Sci Rep 2023; 13:10554. [PMID: 37386285 PMCID: PMC10310833 DOI: 10.1038/s41598-023-37532-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 06/23/2023] [Indexed: 07/01/2023] Open
Abstract
Few articles have reported on the treatment of Masada type 2 forearm deformities in hereditary multiple exostosis, possibly because of the high redislocation rate and other complications. This study precisely declares the use of modified ulnar lengthening by an Ilizarov external fixation with tumour excision for the treatment of Masada type 2 forearm deformities. 20 children with Masada type 2 forearm deformities were admitted for surgical treatment at our hospital from February 2014 to February 2021. There were 13 girls and 7 boys, ranging in age from 3.5 to 15 years (mean: 9 years) at the time of operation. We removed the prominent osteochondromas of the distal ulna and the proximal radius, positioned a classic Ilizarov external fixator on the forearm and then performed ulnar transverse one-third proximal diaphyseal subperiosteal osteotomy. We adopted modified ulnar lengthening postoperatively. The effects of surgical correction of deformity and functional improvement of the limb were assessed via regular follow-up and X-ray. The patients were followed up for 36 months, and the ulna was lengthened 26.99 mm on average; all radial heads remained relocated. The radiographic evaluations, including relative ulnar shortening, radial articular angle, and carpal slip, were improved. The functions of the elbow and forearm were all improved after surgery. Modified ulnar lengthening by an Ilizarov external fixation with tumour excision for the treatment of Masada type 2 forearm deformities in hereditary multiple exostoses has been proven to be an effective and reliable technique in the early stage.
Collapse
Affiliation(s)
- Shu Cao
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Jian-Fa Zeng
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Sheng Xiao
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China.
| | - Zhong-Gen Dong
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Zi-Li Xu
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Hong Liu
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Xin Li
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Ke Fang
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Jie Wen
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Ming Zeng
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Zhong-Wen Tang
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Bo Li
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Hao-Li Gong
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| | - Fan-Ling Li
- Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, People's Republic of China
| |
Collapse
|
|
12
|
Alexandrou A, Salameh N, Papaevripidou I, Nicolaou N, Myrianthopoulos P, Ketoni A, Kousoulidou L, Anastasiou AM, Evangelidou P, Tanteles GA, Sismani C. Hereditary multiple exostoses caused by a chromosomal inversion removing part of EXT1 gene. Mol Cytogenet 2023; 16:8. [PMID: 37217936 DOI: 10.1186/s13039-023-00638-0] [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: 01/10/2023] [Accepted: 05/07/2023] [Indexed: 05/24/2023] Open
Abstract
BACKGROUND Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple, circumscript and usually symmetric bony protuberances called osteochondromas. Most HME are caused by EXT1 and EXT2 loss of function mutations. Most pathogenic mutations are nonsense followed by missense mutations and deletions. CASE PRESENTATION Here we report on a patient with a rare and complex genotype resulting in a typical HME phenotype. Initial point mutation screening in EXT1 and EXT2 genes by Sanger sequencing did not reveal any pathogenic variants. The patient along with the healthy parents was subsequently referred for karyotype and array-Comparative Genomic Hybridization (CGH) analyses. Chromosomal analysis revealed two independent de novo apparently balanced rearrangements: a balanced translocation between the long arms of chromosomes 2 and 3 at breakpoints 2q22 and 3q13.2 and a pericentric inversion with breakpoints at 8p23.1q24.1. Both breakpoints were confirmed by Fluorescence In Situ Hybridization (FISH). Subsequently, array-CGH revealed a novel heterozygous deletion within the EXT1 gene at one of the inversion breakpoints, rendering the inversion unbalanced. The mode of inheritance, as well as the size of the deletion were further investigated by Quantitative Real-time PCR (qPCR), defining the deletion as de novo and of 3.1 kb in size, removing exon 10 of EXT1. The inversion in combination with the 8p23.1 deletion most likely abolishes the transcription of EXT1 downstream of exon 10 hence resulting in a truncated protein. CONCLUSIONS The identification of a rare and novel genetic cause of HME, highlights the importance of additional comprehensive investigation of patients with typical clinical manifestations, even when EXT1 and EXT2 mutation analysis is negative.
Collapse
Affiliation(s)
- Angelos Alexandrou
- Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371, Ayios Dometios, PO Box 23462, 1683, Nicosia, Cyprus
| | - Nicole Salameh
- Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371, Ayios Dometios, PO Box 23462, 1683, Nicosia, Cyprus
| | - Ioannis Papaevripidou
- Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371, Ayios Dometios, PO Box 23462, 1683, Nicosia, Cyprus
| | - Nayia Nicolaou
- Clinical Genetics Department, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Panayiotis Myrianthopoulos
- Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371, Ayios Dometios, PO Box 23462, 1683, Nicosia, Cyprus
| | - Andria Ketoni
- Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371, Ayios Dometios, PO Box 23462, 1683, Nicosia, Cyprus
| | - Ludmila Kousoulidou
- Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371, Ayios Dometios, PO Box 23462, 1683, Nicosia, Cyprus
| | - Anna-Maria Anastasiou
- Clinical Genetics Department, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Paola Evangelidou
- Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371, Ayios Dometios, PO Box 23462, 1683, Nicosia, Cyprus
| | - George A Tanteles
- Clinical Genetics Department, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Carolina Sismani
- Cytogenetics and Genomics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, 2371, Ayios Dometios, PO Box 23462, 1683, Nicosia, Cyprus.
| |
Collapse
|
|
13
|
Pfeifer V, Weber H, Wang Y, Schlesinger M, Gorzelanny C, Bendas G. Exostosin 1 Knockdown Induces Chemoresistance in MV3 Melanoma Cells by Upregulating JNK and MEK/ERK Signaling. Int J Mol Sci 2023; 24:ijms24065452. [PMID: 36982528 PMCID: PMC10049486 DOI: 10.3390/ijms24065452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023] Open
Abstract
Heparan sulfate proteoglycans (HSPGs) possess various functions driving malignancy of tumors. However, their impact on tumor cell sensitivity to cytotoxic treatment is far less understood. Aiming to investigate this, we depleted HSPGs by downregulating Exostosin 1 (EXT1), a key enzyme in HS formation, or upregulating heparanase in human MV3 human melanoma cells, and investigated their response to cytotoxic drugs. Cytotoxicity of trametinib, doxorubicin, and mitoxantrone was detected by MTT assay. Insights into intracellular signaling was provided by kinome protein profiler array, and selected kinases were inhibited to investigate their impact on cell sensitization and migratory dynamics. EXT1 knockdown (EXT1kd) in MV3 cells affected the activity of doxorubicin and mitoxantrone, significantly increasing EC50 values two- or fourfold, respectively. Resistance formation was scarcely related to HSPG deficiency, suggested by enzymatic cleavage of HSPG in control cells. Notably, EXT1kd induced an upregulation of EGFR signaling via JNK and MEK/ERK, and hence blocking these kinases returned resistance to a sensitive level. JNK appeared as a key signal component, also inducing higher migratory activity of EXT1kd cells. Furthermore, EXT1kd upregulated thrombotic properties of MV3 cells, indicated by tissue factor and PAR-1 expression, functionally reflected by a stronger activation of platelet aggregation. EXT1 was confirmed to act as a tumor suppressor, shown here for the first time to affect chemosensitivity of melanoma cells.
Collapse
Affiliation(s)
- Vladlena Pfeifer
- Pharmaceutical Department, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
| | - Heiko Weber
- Pharmaceutical Department, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
| | - Yuanyuan Wang
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Martinistr 52, 20246 Hamburg, Germany
| | - Martin Schlesinger
- Pharmaceutical Department, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
- Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany
| | - Christian Gorzelanny
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Martinistr 52, 20246 Hamburg, Germany
| | - Gerd Bendas
- Pharmaceutical Department, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
- Correspondence: ; Tel.: +49-228-735250
| |
Collapse
|
|
14
|
Abstract
Wnts are secreted proteins that control stem cell maintenance, cell fate decisions, and growth during development and adult homeostasis. Wnts carry a post-translational modification not seen in any other secreted protein: during biosynthesis, they are appended with a palmitoleoyl moiety that is required for signaling but also impairs solubility and hence diffusion in the extracellular space. In some contexts, Wnts act only in a juxtacrine manner but there are also instances of long range action. Several proteins and processes ensure that active Wnts reach the appropriate target cells. Some, like Porcupine, Wntless, and Notum are dedicated to Wnt function; we describe their activities in molecular detail. We also outline how the cell infrastructure (secretory, endocytic, and retromer pathways) contribute to the progression of Wnts from production to delivery. We then address how Wnts spread in the extracellular space and form a signaling gradient despite carrying a hydrophobic moiety. We highlight particularly the role of lipid-binding Wnt interactors and heparan sulfate proteoglycans. Finally, we briefly discuss how evolution might have led to the emergence of this unusual signaling pathway.
Collapse
|
|
15
|
Mundy C, Chung J, Koyama E, Bunting S, Mahimkar R, Pacifici M. Osteochondroma formation is independent of heparanase expression as revealed in a mouse model of hereditary multiple exostoses. J Orthop Res 2022; 40:2391-2401. [PMID: 34996123 PMCID: PMC9259764 DOI: 10.1002/jor.25260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 12/20/2021] [Accepted: 01/05/2022] [Indexed: 02/04/2023]
Abstract
Hereditary multiple exostoses (HME) is a rare, pediatric disorder characterized by osteochondromas that form along growth plates and provoke significant musculoskeletal problems. HME is caused by mutations in heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. Seemingly paradoxically, osteochondromas were found to contain excessive extracellular heparanase (Hpse) that could further reduce HS levels and exacerbate pathogenesis. To test Hpse roles, we asked whether its ablation would protect against osteochondroma formation in a conditional HME model consisting of mice bearing floxed Ext1 alleles in Agr-CreER background (Ext1f/f ;Agr-CreER mice). Mice were crossed with a new global Hpse-null (Hpse-/- ) mice to produce compound Hpse-/- ;Ext1f/f ;Agr-CreER mice. Tamoxifen injection of standard juvenile Ext1f/f ;Agr-CreER mice elicited stochastic Ext1 ablation in growth plate and perichondrium, followed by osteochondroma formation, as revealed by microcomputed tomography and histochemistry. When we examined companion conditional Ext1-deficient mice lacking Hpse also, we detected no major decreases in osteochondroma number, skeletal distribution, and overall structure by the analytical criteria above. The Ext1 mutants used here closely mimic human HME pathogenesis, but have not been previously tested for responsiveness to treatments. To exclude some innate therapeutic resistance in this stochastic model, tamoxifen-injected Ext1f/f ;Agr-CreER mice were administered daily doses of the retinoid Palovarotene, previously shown to prevent ectopic cartilage and bone formation in other mouse disease models. This treatment did inhibit osteochondroma formation compared with vehicle-treated mice. Our data indicate that heparanase is not a major factor in osteochondroma initiation and accumulation in mice. Possible roles of heparanase upregulation in disease severity in patients are discussed.
Collapse
Affiliation(s)
- Christina Mundy
- Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Juliet Chung
- Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Eiki Koyama
- Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | | | | | - Maurizio Pacifici
- Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| |
Collapse
|
|
16
|
Salvadori M, Tsalouchos A. Update on New Antigens in the Pathogenesis of Membranous Nephropathy. EUROPEAN MEDICAL JOURNAL 2022. [DOI: 10.33590/emj/22-00130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Previously, membranous nephropathies were divided into primary and secondary categories when the exact mechanism or pathogenetic factor were unknown.
Approximately 70% accounted for primary membranous nephropathies. The
remaining 30% were called secondary because they developed due to well-known
diseases such as autoimmune diseases, tumours, infections, or drug assumptions.
The discoveries of the M-type phospholipase A2 receptor and of thrombospondin
type 1 domain containing 7A as causative antigens in a part of the so-called primary
membranous nephropathies opened new knowledge on the effective causes of
a large part of these diseases. The availability of novel techniques such as laser
micro-dissection and tandem mass spectrometry, as well as immunochemistry with
antibodies directed against novel proteins, allowed the confirmation of new antigens
involved. The use of confocal microscopy and Western blot allowed detection of the
new antigen on glomerular membrane, and the same antigen and relative antibodies
have been detected in serum samples.
Through these techniques, four new antigens were first detected, including neural
epidermal growth factor 1 and semaphorin 3B in the so-called primary membranous
nephropathy, and exostosin 1 and 2 and neural cell adhesion molecule 1 in lupus
membranous nephropathy.
The aim of this study is to describe the characteristics of the new antigens
discovered and their association with other diseases. In addition, new antigens
are on the horizon, and the story of primary membranous nephropathy is still to be
completely written and understood.
Collapse
Affiliation(s)
| | - Aris Tsalouchos
- Division of Nephrology, Santa Maria Annunziata Hospital, Florence, Italy
| |
Collapse
|
|
17
|
Li H, Lan P, Yu X, Liu X, Sun J, Xie L, Lu W, Xie X. Analysis of the Expression of Exostosins and Clinicopathological Features in Membranous Lupus Nephritis in a Chinese Cohort. Kidney Int Rep 2022; 7:2295-2298. [PMID: 36217518 PMCID: PMC9546740 DOI: 10.1016/j.ekir.2022.07.164] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/11/2022] [Accepted: 07/18/2022] [Indexed: 11/19/2022] Open
Affiliation(s)
- Huixian Li
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ping Lan
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoyang Yu
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoling Liu
- MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Jiping Sun
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Liyi Xie
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Wanhong Lu
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Correspondence: Wanhong Lu, Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, West Yanta Road, Yanta District, Xi’an, Shaanxi 710061, China.
| | - Xinfang Xie
- Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Xinfang Xie, Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, West Yanta Road, Yanta District, Xi’an, Shaanxi 710061, China.
| |
Collapse
|
|
18
|
Matsumoto K, Ogawa H, Komura S, Akiyama H. Functional Impairment of Hip Joint and Activities of Daily Living Failure in Patients with Multiple Hereditary Exostoses. Indian J Orthop 2022; 56:1572-1577. [PMID: 36052379 PMCID: PMC9385922 DOI: 10.1007/s43465-022-00681-w] [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: 11/05/2021] [Accepted: 06/06/2022] [Indexed: 02/04/2023]
Abstract
OBJECTIVE In this study, we focused on the hip joints and examined pain and functional impairment, and their relationship with anatomical characteristics in MHE patients. METHODS Patients with MHE followed up in our hospital from January 2020 to December 2020 were enrolled. Clinical hip functional outcomes were evaluated using the Japanese Orthopedic Association (JOA) hip score and hip range of motion (ROM). Proximal femur geometric measurements were evaluated using radiography. RESULTS A total of 39 patients (78 hips) with a median age of 25.6 years and average JOA score of 94.0 ± 10.5 were included. Eight patients felt pain in their hip joints. The average ROM score was 18.2 ± 2.5, and 47.4% of the patients with MHE had ROM limitation. The average score of ability to walk was 19.6 ± 1.8, and three patients had some problems with walking. The average ADL score was 18.2 ± 2.5, and 51.3% of patients with MHE had some failures in ADL. The hip flexion and internal rotation were markedly restricted compared with the normal values. When patients were grouped according to their ADL scores, we found that the ADL failure group had a significantly lower ROM score than the no ADL failure group (p < 0.0001), and there were significant differences between the groups in terms of femoral neck widening (p = 0.0001). CONCLUSIONS We found that half of MHE patients had some failures in their ADL due to hip functional impairment. The study results also suggest that femoral neck widening affected ADL failure and ROM limitation.
Collapse
Affiliation(s)
- Kazu Matsumoto
- Department of Orthopaedic Surgery, Graduate School of Medicine, Gifu University, 1-1, Yanagido, Gifu, 501-1194 Japan
- Orthopedic Surgery, Gifu Seiryu Hospital, Gifu, Japan
| | - Hiroyasu Ogawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Gifu University, 1-1, Yanagido, Gifu, 501-1194 Japan
- Department of Orthopaedic Surgery, Ogaki Tokushukai Hospital, Gifu, Japan
| | - Shingo Komura
- Department of Orthopaedic Surgery, Graduate School of Medicine, Gifu University, 1-1, Yanagido, Gifu, 501-1194 Japan
| | - Haruhiko Akiyama
- Department of Orthopaedic Surgery, Graduate School of Medicine, Gifu University, 1-1, Yanagido, Gifu, 501-1194 Japan
| |
Collapse
|
|
19
|
Salvadori M, Tsalouchos A. New antigens involved in membranous nephropathy beyond phospholipase A2 receptor. World J Nephrol 2022; 11:115-126. [PMID: 36161266 PMCID: PMC9353762 DOI: 10.5527/wjn.v11.i4.115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/24/2022] [Accepted: 07/08/2022] [Indexed: 02/06/2023] Open
Abstract
When the physiopathology of membranous nephropathy was first described, almost 30% of cases were recognized to be secondary to well-known diseases such as autoimmune diseases, tumors or infections. The remaining 70% cases were called primary membranous nephropathy as the exact mechanism or pathogenic factor involved was unknown. The discovery of the M type phospholipase A2 receptor and thrombospondin type 1 domain containing 7A as causative antigens in these "so called" primary membranous nephropathies provided new insights into the effective causes of a large proportion of these cases. Novel techniques such as laser microdissection and tandem mass spectrometry as well as immunochemistry with antibodies directed against novel proteins allowed the confirmation of new involved antigens. Finally, using confocal microscopy to localize these new antigens and immunoglobulin G and Western blot analysis of serum samples, these new antigens were detected on the glomerular membrane, and the related antibodies were detected in serum samples. The same antigens have been recognized in some cases of secondary membranous disease due to autoimmune diseases, tumors and infections. This has allowed examination of the relationship between antigens in primary membranous nephropathy and their presence in some secondary nephropathies. The aim of this study is to describe the characteristics of the new antigens discovered and their association with other diseases.
Collapse
Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Tuscany, Italy
| | - Aris Tsalouchos
- Division of Nephrology, Santa Maria Annunziata, Florence 50012, Tuscany, Italy
| |
Collapse
|
|
20
|
Functional mechanisms of TRPS1 in disease progression and its potential role in personalized medicine. Pathol Res Pract 2022; 237:154022. [PMID: 35863130 DOI: 10.1016/j.prp.2022.154022] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/04/2022] [Accepted: 07/12/2022] [Indexed: 11/22/2022]
Abstract
The gene of transcriptional repressor GATA binding 1 (TRPS1), as an atypical GATA transcription factor, has received considerable attention in a plethora of physiological and pathological processes, and may become a promising biomarker for targeted therapies in diseases and tumors. However, there still lacks a comprehensive exploration of its functions and promising clinical applications. Herein, relevant researches published in English from 2000 to 2022 were retrieved from PubMed, Google Scholar and MEDLINE, concerning the roles of TRPS1 in organ differentiation and tumorigenesis. This systematic review predominantly focused on summarizing the structural characteristics and biological mechanisms of TRPS1, its involvement in tricho-rhino-phalangeal syndrome (TRPS), its participation in the development of multiple tissues, the recent advances of its vital features in metabolic disorders as well as malignant tumors, in order to prospect its potential applications in disease detection and cancer targeted therapy. From the clinical perspective, the deeply and thoroughly understanding of the complicated context-dependent and cell-lineage-specific mechanisms of TRPS1 would not only gain novel insights into the complex etiology of diseases, but also provide the fundamental basis for the development of therapeutic drugs targeting both TRPS1 and its critical cofactors, which would facilitate individualized treatment.
Collapse
|
|
21
|
Wu H, Zhao X, Zhu T, Rong D, Wang Y, Leng D, Wu D. A Glycosyltransferase-Related Signature for Predicting Overall Survival in Head and Neck Squamous Cell Carcinoma. Front Genet 2022; 13:856671. [PMID: 35899200 PMCID: PMC9311713 DOI: 10.3389/fgene.2022.856671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/30/2022] [Indexed: 01/02/2023] Open
Abstract
Background: Here, we establish a prognostic signature based on glycosyltransferase-related genes (GTRGs) for head and neck squamous cell carcinoma (HNSCC) patients. Methods: The prognostic signature of GTRGs was constructed via univariate and multivariate Cox analyses after obtaining the expression patterns of GTRGs from the TCGA. A nomogram based on the signature and clinical parameters was established to predict the survival of each HNSCC patient. Potential mechanisms were explored through gene set enrichment analysis (GSEA) and immune cell infiltration, immune checkpoints, immunotherapy, and tumor mutational burden (TMB) analyses. The expression differences and prognostic efficacy of the signature were verified through the gene expression omnibus (GEO) and several online databases. Results: The prognostic signature was constructed based on five glycosyltransferases (PYGL, ALG3, EXT2, FUT2, and KDELC1) and validated in the GSE65858 dataset. The pathways enriched in the high- and low-risk groups were significantly different. The high-risk group had higher tumor purity; lower infiltration of immune cells, such as CD8+ T cells and Tregs; higher cancer-associated fibroblast (CAF) infiltration; lower immune function; and lower checkpoint expression. The signature can also be applied to distinguish whether patients benefit from immunotherapy. In addition, the high-risk group had a higher TMB and more gene mutations, including those in TP53, CSMD1, CDKN2A, and MUC17. Conclusion: We propose a prognostic signature based on glycosyltransferases for HNSCC patients that may provide potential targets and biomarkers for the precise treatment of HNSCC.
Collapse
Affiliation(s)
- Huili Wu
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Oral and Maxillofacial Imaging, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Xiao Zhao
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Oral and Maxillofacial Imaging, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Tingting Zhu
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Oral and Maxillofacial Imaging, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Di Rong
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Oral and Maxillofacial Imaging, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Ying Wang
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Oral and Maxillofacial Imaging, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Diya Leng
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Oral and Maxillofacial Imaging, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
| | - Daming Wu
- Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Department of Oral and Maxillofacial Imaging, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China
- Jiangsu Province Key Laboratory of Oral Diseases, Nanjing, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, China
- *Correspondence: Daming Wu,
| |
Collapse
|
|
22
|
Lin Y, Lian L, Zhu Y, Wang L, Li H, Zheng Y, Cai Q, He W, Xie H, Wei Y, Wang H, Xie H, Zhang J. Characterization and expression analysis of the glycosyltransferase 64 familyin rice (Oryza sativa). Gene 2022; 838:146708. [PMID: 35772655 DOI: 10.1016/j.gene.2022.146708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/11/2022] [Accepted: 06/24/2022] [Indexed: 11/04/2022]
Abstract
The glycosyltransferase 64 (GT64) family is widely conserved in many species, including animals and plants. The functions of GT64 family genes in animals have been well characterized in the biosynthesis of extracellular heparan sulfate, whereas two GT64 members in Arabidopsis thaliana are involved in the glycosylation of plasma membrane glycosylinositol phosphorylceramides (GIPCs). GIPCs are the main components of plant sphingolipids and serve as important signal molecules in various developmental processes and stress responses. Rice (Oryza sativa), a model monocot plant, contains four GT64 members in its genome. Using phylogenetic analysis, 73 GT64s from 19 plant species were divided into three main groups. Each group can be represented by the three members in Arabidopsis and show a trend of monocot-eudicot divergences. A promoter and genomic variation analysis of GT64s in rice showed that various stress-related regulatory elements exist in their promoters, and many sequence variations were found between the two main rice subspecies, japonica and indica. Additionally, the transmembrane domain and subcellular localization analyses revealed that these genes all encode membrane-bound glycosyltransferases and localize to the Golgi apparatus. Finally, expression analysis of the four GT64 genes in rice, as assessed by real-time quantitative PCR, showed that they have distinct tissue-specific expression patterns and respond to different hormone treatments or abiotic stresses. Our results indicated that this family of genes may play a role in different stress responses and hormone signaling pathways in rice, and therefore provides fundamental information for the further investigation of their function in rice.
Collapse
Affiliation(s)
- Yuelong Lin
- College of Agronomy, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Ling Lian
- Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Yongsheng Zhu
- Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Lanling Wang
- College of Agronomy, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Hong Li
- College of Agronomy, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Yanmei Zheng
- Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Qiuhua Cai
- Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Wei He
- Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Hongguang Xie
- Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Yidong Wei
- Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Hai Wang
- College of Agronomy, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China
| | - Huaan Xie
- College of Agronomy, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China.
| | - Jianfu Zhang
- College of Agronomy, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Rice Research Institute, Fujian Academy of Agricultural Sciences, Fuzhou 350019, China; State Key Laboratory for Ecological control of Crop Pests between Fujian and Taiwan/National Engineering Laboratory of Rice/South-China Research Base of State Key Laboratory of Hybrid Rice/Incubating base of State Key Laboratory of Crop Germplasm Innovation and Molecular Breeding between Fujian and Ministry of Science and Technology/Fuzhou Branch of National Rice Improvement Center/ Key Laboratory of Hybrid Rice Germplasm innovation and Molecular Breeding of Ministry of Agriculture and Rural Areas for South China /Fujian Engineering Laboratory of Crop Molecular Breeding/Fujian Key Laboratory of Rice Molecular Breeding, Fuzhou 350003, Fujian, China.
| |
Collapse
|
|
23
|
A Genotype-Phenotype Study of Multiple Hereditary Exostoses in Forty-Three Patients. J Clin Med 2022; 11:jcm11133703. [PMID: 35806987 PMCID: PMC9267182 DOI: 10.3390/jcm11133703] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 12/03/2022] Open
Abstract
Multiple hereditary exostoses (MHE) is a rare autosomal dominant skeletal disorder with a variety of clinical manifestations. We aimed to evaluate the general clinical phenotypic severity of MHE using our own scoring system and analyzed the risk factors associated with severe clinical phenotypes. In this study, 43 patients from 30 families were analyzed. The mutations were identified by direct sequencing of polymerase chain reaction-amplified genomic DNA or by multiplex ligation-dependent probe amplification. According to a new scoring system devised by the authors, the severity of the phenotype was assessed as mild, moderate, or severe based on the deformity of each segment, number of exostoses, leg length discrepancy, and functional limitations. Of 43 patients from 30 families, 39 patients (90.7%) and 24 families (80%) presented with EXT1 or EXT2 mutations. Patients with EXT1 mutations had a significantly worse phenotype than that of patients with EXT2 mutations or without any detectable mutation. The mean clinical score of patients with an EXT1 mutation (5.76; range, 2.0–8.0; SD = 1.60) was higher than that of patients with an EXT2 mutation (4.06; range, 2.0–7.0; SD = 1.47) or of those without any detectable mutation (4.63; range, 3.0–6.0; SD = 1.44; p = 0.005). According to our classification system, more patients with EXT1 mutations had ‘severe disease’ than those with EXT2 mutations. Deformity scores were also higher in patients with EXT1 mutations (p = 0.018). In the multivariate analysis, the deformity score was found to be associated with the ‘severe’ class (p = 0.031). In conclusion, 90.7% of patients with MHE showed EXT mutations. Our scoring system showed reliable results. We suggest that the extent of deformity is an important factor in determining the phenotype of MHE and close monitoring for the development of severe disease is recommended in patients with high deformity scores.
Collapse
|
|
24
|
Liu YC, Wierbowski BM, Salic A. Hedgehog pathway modulation by glypican 3-conjugated heparan sulfate. J Cell Sci 2022; 135:274739. [PMID: 35142364 PMCID: PMC8977055 DOI: 10.1242/jcs.259297] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 02/04/2022] [Indexed: 11/20/2022] Open
Abstract
Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson-Golabi-Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation. This article has an associated First Person interview with the first author of the paper.
Collapse
Affiliation(s)
- Yulu Cherry Liu
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.,Department of Biology, Hood College, Frederick, MD 21701, USA
| | | | - Adrian Salic
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| |
Collapse
|
|
25
|
Bukowska-Olech E, Trzebiatowska W, Czech W, Drzymała O, Frąk P, Klarowski F, Kłusek P, Szwajkowska A, Jamsheer A. Hereditary Multiple Exostoses-A Review of the Molecular Background, Diagnostics, and Potential Therapeutic Strategies. Front Genet 2021; 12:759129. [PMID: 34956317 PMCID: PMC8704583 DOI: 10.3389/fgene.2021.759129] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 11/08/2021] [Indexed: 11/17/2022] Open
Abstract
Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder. The disease is characterized by multiple benign cartilage-capped bony outgrowths, termed exostoses or osteochondromas, that locate most commonly in the juxta-epiphyseal portions of long bones. Affected individuals usually complain of persistent pain caused by the pressure on neighboring tissues, disturbance of blood circulation, or rarely by spinal cord compression. However, the most severe complication of this condition is malignant transformation into chondrosarcoma, occurring in up to 3.9% of HMEs patients. The disease results mainly from heterozygous loss-of-function alterations in the EXT1 or EXT2 genes, encoding Golgi-associated glycosyltransferases, responsible for heparan sulfate biosynthesis. Some of the patients with HMEs do not carry pathogenic variants in those genes, hence the presence of somatic mutations, deep intronic variants, or another genes/loci is suggested. This review presents the systematic analysis of current cellular and molecular concepts of HMEs along with clinical characteristics, clinical and molecular diagnostic methods, differential diagnosis, and potential treatment options.
Collapse
Affiliation(s)
| | | | - Wiktor Czech
- Medical Student, Poznan University of Medical Sciences, Poznan, Poland
| | - Olga Drzymała
- Medical Student, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Frąk
- Medical Student, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Piotr Kłusek
- Medical Student, Poznan University of Medical Sciences, Poznan, Poland
| | - Anna Szwajkowska
- Medical Student, Poznan University of Medical Sciences, Poznan, Poland
| | - Aleksander Jamsheer
- Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.,Centers for Medical Genetics GENESIS, Poznan, Poland
| |
Collapse
|
|
26
|
Garcia SA, Ng VY, Iwamoto M, Enomoto-Iwamoto M. Osteochondroma Pathogenesis: Mouse Models and Mechanistic Insights into Interactions with Retinoid Signaling. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:2042-2051. [PMID: 34809786 PMCID: PMC8647428 DOI: 10.1016/j.ajpath.2021.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 07/27/2021] [Accepted: 08/12/2021] [Indexed: 05/02/2023]
Abstract
Osteochondromas are cartilage-capped tumors that arise near growing physes and are the most common benign bone tumor in children. Osteochondromas can lead to skeletal deformity, pain, loss of motion, and neurovascular compression. Currently, surgery is the only available treatment for symptomatic osteochondromas. Osteochondroma mouse models have been developed to understand the pathology and the origin of osteochondromas and develop therapeutic drugs. Several cartilage regulatory pathways have been implicated in the development of osteochondromas, such as bone morphogenetic protein, hedgehog, and WNT/β-catenin signaling. Retinoic acid receptor-γ is an important regulator of endochondral bone formation. Selective agonists for retinoic acid receptor-γ, such as palovarotene, have been investigated as drugs for inhibition of ectopic endochondral ossification, including osteochondromas. This review discusses the signaling pathways involved in osteochondroma pathogenesis and their possible interactions with the retinoid pathway.
Collapse
Affiliation(s)
- Sonia Arely Garcia
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Vincent Y Ng
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Masahiro Iwamoto
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Motomi Enomoto-Iwamoto
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryland.
| |
Collapse
|
|
27
|
Haouari W, Dubail J, Poüs C, Cormier-Daire V, Bruneel A. Inherited Proteoglycan Biosynthesis Defects-Current Laboratory Tools and Bikunin as a Promising Blood Biomarker. Genes (Basel) 2021; 12:genes12111654. [PMID: 34828260 PMCID: PMC8625474 DOI: 10.3390/genes12111654] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/11/2021] [Accepted: 10/17/2021] [Indexed: 12/15/2022] Open
Abstract
Proteoglycans consist of proteins linked to sulfated glycosaminoglycan chains. They constitute a family of macromolecules mainly involved in the architecture of organs and tissues as major components of extracellular matrices. Some proteoglycans also act as signaling molecules involved in inflammatory response as well as cell proliferation, adhesion, and differentiation. Inborn errors of proteoglycan metabolism are a group of orphan diseases with severe and irreversible skeletal abnormalities associated with multiorgan impairments. Identifying the gene variants that cause these pathologies proves to be difficult because of unspecific clinical symptoms, hardly accessible functional laboratory tests, and a lack of convenient blood biomarkers. In this review, we summarize the molecular pathways of proteoglycan biosynthesis, the associated inherited syndromes, and the related biochemical screening techniques, and we focus especially on a circulating proteoglycan called bikunin and on its potential as a new biomarker of these diseases.
Collapse
Affiliation(s)
- Walid Haouari
- INSERM UMR1193, Paris-Saclay University, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92220 Châtenay-Malabry, France; (W.H.); (C.P.)
| | - Johanne Dubail
- INSERM UMR1163, French Reference Center for Skeletal Dysplasia, Imagine Institute, Paris University, 24 Boulevard du Montparnasse, 75015 Paris, France; (J.D.); (V.C.-D.)
- AP-HP, Necker Enfants Malades Hospital, 149 rue de Sèvres, 75015 Paris, France
| | - Christian Poüs
- INSERM UMR1193, Paris-Saclay University, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92220 Châtenay-Malabry, France; (W.H.); (C.P.)
| | - Valérie Cormier-Daire
- INSERM UMR1163, French Reference Center for Skeletal Dysplasia, Imagine Institute, Paris University, 24 Boulevard du Montparnasse, 75015 Paris, France; (J.D.); (V.C.-D.)
- AP-HP, Necker Enfants Malades Hospital, 149 rue de Sèvres, 75015 Paris, France
| | - Arnaud Bruneel
- INSERM UMR1193, Paris-Saclay University, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, 92220 Châtenay-Malabry, France; (W.H.); (C.P.)
- AP-HP, Biochimie Métabolique et Cellulaire, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France
- Correspondence:
| |
Collapse
|
|
28
|
Zhang F, Wang Y, Wang Y, Wang X, Zhang D, Zhao X, Jiang R, Gu Y, Yang G, Fu X, Xu L, Xu L, Zheng L, Zhang J, Li Z, Yan Q, Shi J, Roessner A, Wang Z, Li Q, Ye J, Chen CD, Guo S, Min J. Disruption of Jmjd3/p16 Ink4a Signaling Pathway Causes Bizarre Parosteal Osteochondromatous Proliferation (BPOP)-like Lesion in Mice. J Bone Miner Res 2021; 36:1931-1941. [PMID: 34173271 DOI: 10.1002/jbmr.4401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 06/16/2021] [Accepted: 06/20/2021] [Indexed: 11/06/2022]
Abstract
Bizarre parosteal osteochondromatous proliferation (BPOP), or Nora's lesion, is a rare benign osteochondromatous lesion. At present, the molecular etiology of BPOP remains unclear. JMJD3(KDM6B) is an H3K27me3 demethylase and counteracts polycomb-mediated transcription repression. Previously, Jmjd3 was shown to be critical for bone development and osteoarthritis. Here, we report that conditional deletion of Jmjd3 in chondrogenic cells unexpectedly resulted in BPOP-like lesion in mice. Biochemical investigations revealed that Jmjd3 inhibited BPOP-like lesion through p16Ink4a . Immunohistochemistry and RT-qPCR assays indicated JMJD3 and p16INK4A level were significantly reduced in human BPOP lesion compared with normal subjects. This was further confirmed by Jmjd3/Ink4a double-gene knockout mice experiments. Therefore, our results indicated the pathway of Jmjd3/p16Ink4a may be essential for the development of BPOP in human. © 2021 American Society for Bone and Mineral Research (ASBMR).
Collapse
Affiliation(s)
- Feng Zhang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.,Department of Pathology, Air Force Medical Center (Air Force General Hospital), PLA, Beijing, China
| | - Yingmei Wang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yuying Wang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xinli Wang
- Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Dawei Zhang
- Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xiong Zhao
- Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Runmin Jiang
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yu Gu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Guifang Yang
- Department of Surgery, Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xin Fu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Longyong Xu
- State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Longxia Xu
- State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Liting Zheng
- State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jing Zhang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Zengshan Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Qingguo Yan
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jianguo Shi
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Albert Roessner
- Department of Pathology, Otto-von-Guericke University, Magdeberg, Germany
| | - Zhe Wang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Qing Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jing Ye
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Charlie Degui Chen
- State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Shuangping Guo
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jie Min
- Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
29
|
Mizumoto S, Yamada S. Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis. Front Genet 2021; 12:717535. [PMID: 34539746 PMCID: PMC8446454 DOI: 10.3389/fgene.2021.717535] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/12/2021] [Indexed: 12/04/2022] Open
Abstract
Glycosaminoglycans (GAGs) including chondroitin sulfate, dermatan sulfate, and heparan sulfate are covalently attached to specific core proteins to form proteoglycans, which are distributed at the cell surface as well as in the extracellular matrix. Proteoglycans and GAGs have been demonstrated to exhibit a variety of physiological functions such as construction of the extracellular matrix, tissue development, and cell signaling through interactions with extracellular matrix components, morphogens, cytokines, and growth factors. Not only connective tissue disorders including skeletal dysplasia, chondrodysplasia, multiple exostoses, and Ehlers-Danlos syndrome, but also heart and kidney defects, immune deficiencies, and neurological abnormalities have been shown to be caused by defects in GAGs as well as core proteins of proteoglycans. These findings indicate that GAGs and proteoglycans are essential for human development in major organs. The glycobiological aspects of congenital disorders caused by defects in GAG-biosynthetic enzymes including specific glysocyltransferases, epimerases, and sulfotransferases, in addition to core proteins of proteoglycans will be comprehensively discussed based on the literature to date.
Collapse
Affiliation(s)
- Shuji Mizumoto
- Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Shuhei Yamada
- Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| |
Collapse
|
|
30
|
Mordenti M, Gnoli M, Boarini M, Trisolino G, Evangelista A, Pedrini E, Corsini S, Tremosini M, Staals EL, Antonioli D, Stilli S, Donati DM, Sangiorgi L. The Rizzoli Multiple Osteochondromas Classification revised: describing the phenotype to improve clinical practice. Am J Med Genet A 2021; 185:3466-3475. [PMID: 34477285 PMCID: PMC9293117 DOI: 10.1002/ajmg.a.62470] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 07/29/2021] [Accepted: 08/05/2021] [Indexed: 11/07/2022]
Abstract
Multiple osteochondromas (MO) is a rare disorder, characterized by benign osteocartilaginous tumors (osteochondromas), arising from the perichondrium of bones. The osteochondromas increase during growth, frequently causing deformities and limitations. Our study aims to analyze the data captured by the Registry of Multiple Osteochondromas, to refine Istituto Ortopedico Rizzoli (IOR) Classification, providing a representative picture of the phenotypic manifestations throughout the lifespan. We conducted a single‐institution cross‐sectional study. Patients were categorized according to IOR Classification, which identifies three patients' classes on the presence/absence of deformities and/or limitations. The present dataset was compared with our previously published data, to refine the classification. Nine hundred sixty‐eight patients were included: 243 children (<10 years), 136 adolescents (10–15 years), and 589 adults. Of the entire population, half patients presented at least one deformity, and one quarter reported at least one limitation. Compared with our previous study, the amount of children was more than doubled and the percentage of mild/moderate cases was notably increased, giving a better disease overview throughout the lifespan and suggesting a different cut‐off for dividing Class II in subclasses. We confirmed that MO is characterized by phenotypic heterogeneity, suggesting that an early classification of the disease may offer a useful tool to follow disease pattern and evolution, to support clinical practice, and to propose timely interventions.
Collapse
Affiliation(s)
- Marina Mordenti
- Department of Rare Skeletal DisordersIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Maria Gnoli
- Department of Rare Skeletal DisordersIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Manila Boarini
- Department of Rare Skeletal DisordersIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Giovanni Trisolino
- Unit of Pediatric Orthopedics and Traumatology, IRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Andrea Evangelista
- Department of Rare Skeletal DisordersIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Elena Pedrini
- Department of Rare Skeletal DisordersIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Serena Corsini
- Department of Rare Skeletal DisordersIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Morena Tremosini
- Department of Rare Skeletal DisordersIRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Eric L. Staals
- Department of Third Orthopedic and Traumatologic Clinic prevalently Oncologic, IRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Diego Antonioli
- Unit of Pediatric Orthopedics and Traumatology, IRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Stefano Stilli
- Unit of Pediatric Orthopedics and Traumatology, IRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Davide M. Donati
- Department of Third Orthopedic and Traumatologic Clinic prevalently Oncologic, IRCCS Istituto Ortopedico RizzoliBolognaItaly
| | - Luca Sangiorgi
- Department of Rare Skeletal DisordersIRCCS Istituto Ortopedico RizzoliBolognaItaly
| |
Collapse
|
|
31
|
Yang M, Xie H, Xu B, Xiang Q, Wang H, Hu T, Liu S. Identification of a novel EXT2 frameshift mutation in a family with hereditary multiple exostoses by whole-exome sequencing. J Clin Lab Anal 2021; 35:e23968. [PMID: 34403521 PMCID: PMC8418499 DOI: 10.1002/jcla.23968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 08/04/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hereditary multiple exostoses (HME), also referred to as multiple osteochondromas, is an autosomal dominant skeletal disease characterized by the development of multiple overgrown benign bony tumors capped by cartilage and is associated with bone deformity, joint limitation, and short stature. Mutations in exostosin glycosyltransferase (EXT)1 and EXT2 genes, which are located on chromosomes 8q24.1 and 11p13, contribute to the pathogenesis of HME. METHODS In the present study, a genetic analysis of a four-generation Chinese family with HME was conducted using whole-exome sequencing (WES), followed by validation using Sanger sequencing. RESULTS A novel heterozygous frameshift mutation in exon 5 of EXT2 (c.944dupT, p.Leu316fs) was identified in all affected individuals but was not detected in any unaffected individuals. This mutation results in a frameshift that introduces a premature termination codon at position 318 (p.Leu316fs) with the ability to produce a truncated EXT2 protein that lacks the last 433 amino acids at its C-terminal to indicate a defective exostosin domain and the absence of the glycosyltransferase family 64 domain, or to lead to the degradation of mRNAs by nonsense-mediated mRNA decay, which is critical for the function of EXT2. CONCLUSION Our results indicate that WES is effective in extending the EXT mutational spectra and is advantageous for genetic counseling and the subsequent prenatal diagnosis.
Collapse
Affiliation(s)
- Mei Yang
- Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China
| | - Hanbing Xie
- Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China
| | - Bocheng Xu
- Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China
| | - Qinqin Xiang
- Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China
| | - He Wang
- Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China
| | - Ting Hu
- Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China
| | - Shanling Liu
- Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, Sichuan, China
| |
Collapse
|
|
32
|
Tong Y, Zhang Y, Luo J, Hong Z, Chen X, Bi Q. Identification of Novel Mutations in the EXT1 and EXT2 Genes of Chinese Patients with Hereditary Multiple Osteochondromas. Genet Test Mol Biomarkers 2021; 25:145-151. [PMID: 33596140 DOI: 10.1089/gtmb.2020.0098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Aim: To detect mutations in the EXT1 and EXT2 genes in four Chinese families with hereditary multiple osteochondromas (HMO). HMO is an autosomal dominant disorder characterized by the overgrowth of multiple cartilage-capped bones in the metaphysis of long bones and flat bones. Methods: Polymerase chain reaction-based amplification followed by DNA sequencing of the complete coding sequences of EXT1 and EXT2 was performed for four Chinese families with HMO. Results: The mutant allele was found in six patients: three mutations were found in EXT1 and two in EXT2. A novel frameshift mutation, which generates a premature stop codon at codon 586 and causes partial loss of the glycosyltransferase domain, was detected in exon 9 of EXT1 (F579Yfs*8). We hypothesize that F579Yfs*8 is a pathogenic mutation. Two novel missense mutations (G339S and V545D) were found in EXT1. The variant c.1634T>A (V545D) is apparently benign. In addition we found a novel deletion mutation in EXT2, c.856_864 del TTCCTCCTG, which results in the deletion of 286Phe, 287Leu, and 288Leu, that is likely pathogenic. Finally, we identified a likely benign variant in exon 13 of EXT2. c.2035-41T>C (rs3740878). Conclusions: We found three novel, potentially pathogenic mutations in EXT1 and EXT2, including a novel frameshift mutation. More importantly, our study results have expanded the spectrum of EXT mutations conducive to the genetic diagnosis and counseling of patients with HMO.
Collapse
Affiliation(s)
- Yu Tong
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yin Zhang
- Graduate Department, Bengbu Medical College, Bengbu, China
| | - Junchao Luo
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zheping Hong
- Department of Orthopedic Surgery, Zhejiang Provincial People's Hospital and People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xinji Chen
- Department of Orthopedic Surgery, Zhejiang Provincial People's Hospital and People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qing Bi
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Orthopedic Surgery, Zhejiang Provincial People's Hospital and People's Hospital of Hangzhou Medical College, Hangzhou, China
| |
Collapse
|
|
33
|
Guo X, Chen S, Lin M, Pan Y, Liu N, Shi T. A Novel Intronic Splicing Mutation in the EXT2 Gene of a Chinese Family with Multiple Osteochondroma. Genet Test Mol Biomarkers 2021; 25:478-485. [PMID: 34280007 DOI: 10.1089/gtmb.2021.0030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Multiple osteochondroma (MO), an autosomal dominant genetic disease, is caused by heterozygous mutations in the EXT1 and EXT2 genes. Approximately 80% of pathogenic mutations are nonsense/missense mutations, small indels, and splicing mutations. Splicing mutations, particularly at the 3' and 5' splice sites, disrupt normal mRNA processing and cause exon skipping or aberrant splicing, ultimately resulting in protein truncation and loss of function. Methods: Polymerase chain reaction (PCR) and Sanger sequencing were applied to detect subtle mutations in a Chinese family with MO, the pathogenicity of a splicing variant was predicted by bioinformatics and further verified using a minigene splicing assay. Results: A novel and heterozygous splicing mutation, c.626 + 2_626 + 5delTAGG, was identified in the EXT2 gene of the proband and the father by PCR and Sanger sequencing, whereas the unaffected mother and brother had wild-type alleles at the same site. Bioinformatics predicted that the 5' splicing site of exon 3 in the EXT2 gene was destroyed due to this mutation. A hybrid minigene splicing assay (HMSA) indicated that the mutation disturbed the normal splicing of the EXT2 gene mRNA and led to a deletion of 79 bp at the 5' end of exon 3, which resulted in aberrant splicing of exon 3 and introduced an earlier stop codon in the EXT2 gene. Conclusion: A novel splicing mutation was identified that produced the MO phenotype through aberrant splicing in a Chinese family. This observation, expands our knowledge of the spectrum of molecular pathogenic mechanisms leading to aberrant mRNA splicing.
Collapse
Affiliation(s)
- Xiaoyan Guo
- Department of Laboratory Medicine, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, P.R. China
| | - Shunyou Chen
- Department of Orthopedics, and Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, P.R. China
| | - Mingrui Lin
- Intensive Care Unit, The Affiliated People's Hospital of Fujian Traditional Medical University, Fuzhou, P.R. China
| | - Yuancheng Pan
- Department of Orthopedics, and Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, P.R. China
| | - Nannan Liu
- Department of Orthopedics Institute, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, P.R. China
| | - Tengfei Shi
- Department of Laboratory Medicine, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, P.R. China
| |
Collapse
|
|
34
|
Lee DH, Paley D. Reconstruction of the Hip in Multiple Hereditary Exostoses. CHILDREN-BASEL 2021; 8:children8060490. [PMID: 34201373 PMCID: PMC8229271 DOI: 10.3390/children8060490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/03/2021] [Accepted: 06/06/2021] [Indexed: 11/16/2022]
Abstract
The hip joint involvement in multiple hereditary exostoses (MHE) occurs in 30-90%, causing pain and limitation of motion by femoroacetabular impingement, coxa valga, acetabular dysplasia, hip joint subluxation, and osteoarthritis. The purpose of this study was to investigate the clinical and radiographic outcomes of ten hips in seven patients treated by surgical dislocation and corrective osteotomies between 2004 and 2009. Surgical dislocation and excision of the osteochondromas and varus intertrochanteric osteotomies were performed in all cases when the neck-shaft angle was > 150°. Common sites of osteochondromas were medial, posterior, and anterior neck of the femur. Neck-shaft angle of the femur was improved from a mean of 157° to 139°, postoperatively. On an average, the center-edge angle improved from 20° to 30° postoperatively. We believe that Ganz's safe surgical dislocation technique is the preferred treatment of MHE. This safeguards the circulation of the femoral head and the osteochondromas can be resected under direct vision. It can be combined with additional corrective osteotomies because the hip affected by MHE is frequently associated with dysplastic changes which can result in premature osteoarthritis.
Collapse
Affiliation(s)
- Dong Hoon Lee
- Donghoon Advanced Lengthening Reconstruction Institute, Superstar tower 3-5F 10, Wiryeseoil-ro, Sujeong-gu, Seongnam-si 11962, Gyeonggi-do, Korea;
| | - Dror Paley
- Paley Orthopedic and Spine Institute, Kimmel, 901 45th St, West Palm Beach, FL 33407, USA
- Correspondence: ; Tel.: +1-561-844-5255; Fax: +1-561-844-5245
| |
Collapse
|
|
35
|
Matsumoto K, Ishimaru D, Ogawa H, Komura S, Shimizu K, Akiyama H. Correlation between mutated genes and forearm deformity in patients with multiple osteochondroma. J Orthop Sci 2021; 26:483-486. [PMID: 32636136 DOI: 10.1016/j.jos.2020.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/15/2020] [Accepted: 05/07/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUNDS Exostosin-1 (EXT1) and exostosin-2 (EXT2) cause multiple osteochondromas (MO). In this study, we investigated the correlation between forearm deformity and mutant EXTs in Japanese families with MO. METHODS We evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. Of these, 28 patients were selected and underwent radiography for their forearms since they had gross forearm deformities. We measured the radial articular angle (RAA), ulna variance (UV), carpal slip (CS), and percentage of radial bowing (%RB) to compare between patients with mutant EXT1 or EXT2 and those with missense or other mutations using Student's t-test. RESULTS Twenty-two (78.6%) and 6 (11.4%) out of 28 patients had mutations in EXT1 and EXT2, respectively. Nine (32.1%) and 19 (67.9%) of the 28 patients had missense and other mutations, respectively. The mean age of patients with EXT1 and EXT2 were 25.9 ± 20.3 and 33.5 ± 25.4 years, respectively and those with missense mutation and other mutations were 28.7 ± 27.0 and 24.6 ± 17.0 years, respectively. There were no significant differences in RAA, UV, and RB between patients harbouring mutant EXT1 or EXT2 (RAA, 40.1 ± 8.7 and 31.5 ± 13.9°; UV, -2.7 ± 5.7 and -3.1 ± 3.7 mm; %RB, 8.6 ± 1.5 and 8.3 ± 2.0%). CS was significantly greater in patients with mutant EXT1 than that in those with mutant EXT2 (EXT1, 44.1 ± 16.8%; EXT2, 18.6 ± 14.0%). There were no significant differences in RAA, UV, CS and %RB between patients with missense and other mutations. CONCLUSIONS Patients with mutant EXT1 displayed greater CS than patients with mutant EXT2, indicating that patients with MO harbouring EXT1 mutations sustain more severe ulnar drift deformities than those with EXT2 mutations.
Collapse
Affiliation(s)
- Kazu Matsumoto
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan.
| | - Daichi Ishimaru
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan; Department of Orthopaedic Surgery, Gujo Municipal Hospital, Gifu, Japan
| | - Hiroyasu Ogawa
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan
| | - Shingo Komura
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan
| | - Katsuji Shimizu
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan; Department of Orthopaedic Surgery, Gifu Municipal Hospital, Japan
| | - Haruhiko Akiyama
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, Gifu, Japan
| |
Collapse
|
|
36
|
Mechanisms of Primary Membranous Nephropathy. Biomolecules 2021; 11:biom11040513. [PMID: 33808418 PMCID: PMC8065962 DOI: 10.3390/biom11040513] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022] Open
Abstract
Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome. The disease exhibits heterogenous outcomes with approximately 30% of cases progressing to end-stage renal disease. The clinical management of MN has steadily advanced owing to the identification of autoantibodies to the phospholipase A2 receptor (PLA2R) in 2009 and thrombospondin domain-containing 7A (THSD7A) in 2014 on the podocyte surface. Approximately 50–80% and 3–5% of primary MN (PMN) cases are associated with either anti-PLA2R or anti-THSD7A antibodies, respectively. The presence of these autoantibodies is used for MN diagnosis; antibody levels correlate with disease severity and possess significant biomarker values in monitoring disease progression and treatment response. Importantly, both autoantibodies are causative to MN. Additionally, evidence is emerging that NELL-1 is associated with 5–10% of PMN cases that are PLA2R- and THSD7A-negative, which moves us one step closer to mapping out the full spectrum of PMN antigens. Recent developments suggest exostosin 1 (EXT1), EXT2, NELL-1, and contactin 1 (CNTN1) are associated with MN. Genetic factors and other mechanisms are in place to regulate these factors and may contribute to MN pathogenesis. This review will discuss recent developments over the past 5 years.
Collapse
|
|
37
|
Kannan S, Lock I, Ozenberger BB, Jones KB. Genetic drivers and cells of origin in sarcomagenesis. J Pathol 2021; 254:474-493. [DOI: 10.1002/path.5617] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/01/2020] [Accepted: 01/06/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Sarmishta Kannan
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Ian Lock
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Benjamin B Ozenberger
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| | - Kevin B Jones
- Departments of Orthopaedics and Oncological Sciences Huntsman Cancer Institute, University of Utah School of Medicine Salt Lake City UT USA
| |
Collapse
|
|
38
|
Li L, Yang Z, Tao T, Yang M, Hu ZX. Treatment of exostosin 1-associated membranous lupus nephritis with multiple low doses of rituximab: A case report. Medicine (Baltimore) 2021; 100:e24887. [PMID: 33655949 PMCID: PMC7939150 DOI: 10.1097/md.0000000000024887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 02/04/2021] [Indexed: 02/05/2023] Open
Abstract
RATIONALE Membranous glomerulonephritis (MN) is the leading cause of nephrotic syndrome in adults and is classified as primary or secondary. Secondary MN accounts for 20% to 30% of all MN cases and can arise from a number of conditions, including autoimmune diseases. Recently exostosin 1/exostosin 2 (EXT1/EXT2) have been identified as the common antigens in secondary autoimmune MN and are present in cases of pure membranous lupus nephritis (LN). The treatment of EXT1/EXT2-associated MN remains elusive. PATIENT CONCERNS We present the case of a 15-year-old female who presented with nephrotic syndrome, positive ANA and dsDNA, and low serum complements. A renal biopsy revealed pure membranous nephritis with IgG and C3 deposition. EXT1 was found along the glomerular capillary walls and stained positive, while phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were negative. DIAGNOSIS The patient was diagnosed with ETX1-associated membranous LN. INTERVENTIONS She was treated with prednisone and multiple low-dose rituximab (4 200 mg doses, approximately every 2 months, based on CD19+ cells counts). OUTCOMES The patient had complete remission within 8 months later, and she remained in remission for the 16-month period of follow-up. LESSONS To our knowledge, this is the first case of EXT1-associated MN that has been successfully treated by multiple low-dose rituximab. Further studies can investigate the optimal dosage and treatment protocol.
Collapse
Affiliation(s)
- Ling Li
- Renal Division, Department of Medicine
| | - Zhi Yang
- Renal Division, Department of Medicine
| | - Tian Tao
- Renal Division, Department of Medicine
| | - Mei Yang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | | |
Collapse
|
|
39
|
Ravindran A, Casal Moura M, Fervenza FC, Nasr SH, Alexander MP, Fidler ME, Herrera Hernandez LP, Zhang P, Grande JP, Cornell LD, Gross LA, Negron V, Jenson GE, Madden BJ, Charlesworth MC, Sethi S. In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes. J Am Soc Nephrol 2021; 32:695-706. [PMID: 33478971 PMCID: PMC7920177 DOI: 10.1681/asn.2020081181] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 11/08/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis. METHODS We conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared. RESULTS Our study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger (P=0.01), had significantly lower serum creatinine levels (P=0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h (P=0.009), and had significantly less chronicity features (glomerulosclerosis, P=0.001 or interstitial fibrosis and tubular atrophy, P<0.001) on kidney biopsy. Clinical follow-up data were available for 160 patients, of which 64 (40%) biopsy results were EXT1/EXT2-positive and 96 (60%) were EXT1/EXT2-negative. The proportion of patients with class 3/4 lupus nephritis coexisting with membranous lupus nephritis was not different between the EXT1/EXT2-positive and EXT1/EXT2-negative groups (25.0% versus 32.3%; P=0.32). The patients who were EXT1/EXT2-negative evolved to ESKD faster and more frequently compared with EXT1/EXT2-positive patients (18.8% versus 3.1%; P=0.003). CONCLUSIONS The prevalence of EXT1/EXT2 positivity was 32.6% in our cohort of membranous lupus nephritis. Compared with EXT1/EXT2-negative membranous lupus nephritis, EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices. Cases of membranous lupus nephritis that are EXT1/EXT2-negative are more likely to progress to ESKD compared with those that are EXT1/EXT2-positive.
Collapse
Affiliation(s)
- Aishwarya Ravindran
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Marta Casal Moura
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Samih H. Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Mariam P. Alexander
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Mary E. Fidler
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Pingchuan Zhang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Joseph P. Grande
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Lynn D. Cornell
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Lou Ann Gross
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Vivian Negron
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Grace E. Jenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Benjamin J. Madden
- Medical Genome Facility, Proteomics Core, Mayo Clinic, Rochester, Minnesota
| | | | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
40
|
Al-Zayed Z, Al-Rijjal RA, Al-Ghofaili L, BinEssa HA, Pant R, Alrabiah A, Al-Hussainan T, Zou M, Meyer BF, Shi Y. Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses. Orphanet J Rare Dis 2021; 16:100. [PMID: 33632255 PMCID: PMC7905910 DOI: 10.1186/s13023-021-01738-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 02/11/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors, which are caused by mutations in the genes for exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2). The genetic defects have not been studied in the Saudi patients. AIM OF STUDY We investigated mutation spectrum of EXT1 and EXT2 in 22 patients from 17 unrelated families. METHODS Genomic DNA was extracted from peripheral leucocytes. The coding regions and intron-exon boundaries of both EXT1 and EXT2 genes were screened for mutations by PCR-sequencing analysis. Gross deletions were analyzed by MLPA analysis. RESULTS EXT1 mutations were detected in 6 families (35%) and 3 were novel mutations: c.739G > T (p. E247*), c.1319delG (p.R440Lfs*4), and c.1786delA (p.S596Afs*25). EXT2 mutations were detected in 7 families (41%) and 3 were novel mutations: c.541delG (p.D181Ifs*89), c.583delG (p.G195Vfs*75), and a gross deletion of approximately 10 kb including promoter and exon 1. Five patients from different families had no family history and carried de novo mutations (29%, 5/17). No EXT1 and EXT2 mutations were found in the remaining four families. In total, EXT1 and EXT2 mutations were found in 77% (13/17) of Saudi HME patients. CONCLUSION EXT1 and EXT2 mutations contribute significantly to the pathogenesis of HME in the Saudi population. In contrast to high mutation rate in EXT 1 (65%) and low mutation rate in EXT2 (25%) in other populations, the frequency of EXT2 mutations are much higher (41%) and comparable to that of EXT1 among Saudi patients. De novo mutations are also common and the six novel EXT1/EXT2 mutations further expands the mutation spectrum of HME.
Collapse
Affiliation(s)
- Zayed Al-Zayed
- Department of Orthopedics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Roua A Al-Rijjal
- Department of Genetics, MBC 3, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia
| | | | - Huda A BinEssa
- Department of Genetics, MBC 3, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia
| | - Rajeev Pant
- Department of Orthopedics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Anwar Alrabiah
- Department of Orthopedics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Thamer Al-Hussainan
- Department of Orthopedics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Minjing Zou
- Department of Genetics, MBC 3, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia
| | - Brian F Meyer
- Department of Genetics, MBC 3, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia
| | - Yufei Shi
- Department of Genetics, MBC 3, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.
| |
Collapse
|
|
41
|
Abstract
Membranous nephropathy (MN) occurs due to deposition of immune complexes along the subepithelial region of glomerular basement membrane. Two previously identified target antigens for the immune complexes, PLA2R (identified in 2009) and THSD7A (in 2014), account for approximately 60% of all MN, both primary and secondary. In the remaining MN, target antigens were unknown. Use of laser microdissection and mass spectrometry enabled identification of new "antigens." This approach led to the identification of four novel types of MN: exotosin 1 (EXT1)- and exotosin 2 (EXT2)-associated MN, NELL1-associated MN, Sema3B-associated MN, and PCDH7-associated MN. Each of these represents a distinct disease entity, with different clinical and pathologic findings. In this review, the structure of the proteins and the clinical and pathologic findings of the new types of MN are discussed. The role of mass spectrometry for accurate diagnosis of MN cannot be overemphasized. Finally, any classification of MN should be made on the basis of the antigens that are detected. Further studies are required to understand the pathophysiology, response to treatment, and outcomes of these new MNs.
Collapse
Affiliation(s)
- Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
42
|
Wang Y, Zhong L, Xu Y, Ding L, Ji Y, Schutz S, Férec C, Cooper DN, Xu C, Chen JM, Luo Y. EXT1 and EXT2 Variants in 22 Chinese Families With Multiple Osteochondromas: Seven New Variants and Potentiation of Preimplantation Genetic Testing and Prenatal Diagnosis. Front Genet 2020; 11:607838. [PMID: 33414810 PMCID: PMC7783290 DOI: 10.3389/fgene.2020.607838] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/02/2020] [Indexed: 11/13/2022] Open
Abstract
Multiple osteochondromas (MO), the most common type of benign bone tumor, is an autosomal dominant skeletal disorder characterized by multiple cartilage-capped bony protuberances. In most cases, EXT1 and EXT2, which encode glycosyltransferases involved in the biosynthesis of heparan sulfate, are the genes responsible. Here we describe the clinical, phenotypic and genetic characterization of MO in 22 unrelated Chinese families involving a total of 60 patients. Variant detection was performed by means of a battery of different techniques including Sanger sequencing and whole-exome sequencing (WES). The pathogenicity of the missense and splicing variants was explored by means of in silico prediction algorithms. Sixteen unique pathogenic variants, including 10 in the EXT1 gene and 6 in the EXT2 gene, were identified in 18 (82%) of the 22 families. Fourteen (88%) of the 16 variants were predicted to give rise to truncated proteins whereas the remaining two were missense. Seven variants were newly described here, further expanding the spectrum of MO-causing variants in the EXT1 and EXT2 genes. More importantly, the identification of causative variants allowed us to provide genetic counseling to 8 MO patients in terms either of preimplantation genetic testing (PGT) or prenatal diagnosis, thereby preventing the reoccurrence of MO in the corresponding families. This study is the first to report the successful implementation of PGT in MO families and describes the largest number of subjects undergoing prenatal diagnosis to date.
Collapse
Affiliation(s)
- Ye Wang
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liangying Zhong
- Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan Xu
- Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Reproductive Medicine, Guangzhou, China
| | - Lei Ding
- Department of Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuanjun Ji
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sacha Schutz
- Inserm, Univ Brest, EFS, UMR 1078, GGB, Brest, France
- CHRU Brest, Brest, France
| | - Claude Férec
- Inserm, Univ Brest, EFS, UMR 1078, GGB, Brest, France
- CHRU Brest, Brest, France
| | - David N. Cooper
- School of Medicine, Institute of Medical Genetics, Cardiff University, Cardiff, United Kingdom
| | - Caixia Xu
- Research Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jian-Min Chen
- Inserm, Univ Brest, EFS, UMR 1078, GGB, Brest, France
| | - Yanmin Luo
- Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
43
|
Trombetta A, Migliarino V, Faletra F, Barbi E, Tornese G. An unusual diagnosis for an usual test. Ital J Pediatr 2020; 46:81. [PMID: 32522262 PMCID: PMC7285577 DOI: 10.1186/s13052-020-00846-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/03/2020] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hereditary multiple osteochondromas (HMO) is a genetic condition characterized by the presence of multiple osteochondromas, usually at the lateral side of the most active growth plate of a long bone. These lesions may persist, be asymptomatic during childhood, and may increase in number and size until growth plates close. Therefore, diagnosis of HMO in children and young people can be challenging; while short stature can be more evident at the onset of puberty, asymptomatic ostheocondromas can progress into different degrees of orthopedic deformity. Moreover, multiple complications may arise due to the presence of osteochondromas, including tendon and compression muscle pain, neurovascular disorders, obstetric problems, scoliosis and malignant transformation into secondary peripheral chondrosarcoma in adulthood.
Case presentation
We report the case of a girl admitted to our Institute for growth delay. While laboratory tests, including growth hormone stimulation test, were normal, left hand X-ray revealed multiple osteochondromas, suggestive for HMO. The genetic test for EXT1 and EXT2 genes confirmed the radiological diagnosis, with a mutation inherited from the mother who displayed the same radiological abnormalities along with recurrent limb pain episodes.
Conclusions
HMO is a genetic condition whose diagnosis can be challenging, especially in females. Every pediatricians should consider a skeletal dysplasia in case of unexplained growth delay and a skeletal survey might be fundamental in reaching a diagnosis.
Collapse
|
|
44
|
Matsumoto K, Ogawa H, Nozawa S, Akiyama H. An analysis of osteoporosis in patients with hereditary multiple exostoses. Osteoporos Int 2020; 31:2355-2361. [PMID: 32642853 DOI: 10.1007/s00198-020-05533-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 07/01/2020] [Indexed: 11/30/2022]
Abstract
UNLABELLED We analyzed osteoporosis in 20 HME patients. According to the T-score of BMD, 30% and 67.5% of the patients fell in the range of osteopenia in the lumbar spine and femoral neck. Our results indicate HME patients have low bone mass. They do not have abnormal bone metabolism. INTRODUCTION There are few reports of osteoporosis in hereditary multiple exostoses (HME) patients. Therefore, the purpose of this study was to analyze osteoporosis in HME patients. METHODS This retrospective cohort study included 20 patients diagnosed with HME. Patients underwent bone mineral density (BMD) measurement of the lumbar spine (n = 20) and femoral neck (n = 40). Bone metabolic parameters, including serum osteocalcin and urinary cross-linked N-telopeptide of type 1 collagen (NTx), were analyzed in all subjects. EXT1 and EXT2 genes were sequenced using genomic DNA. We also examined the correlation between genotype and BMD Z-score and T-score. RESULTS The mean BMD values of the lumbar spine were 1.085 ± 0.116 g/cm2 (n = 11) in male and 1.108 ± 0.088 g/cm2 (n = 9) in female. The mean BMD values of the femoral neck area were 0.759 ± 0.125 g/cm2 (n = 22) in male and 0.749 ± 0.115 g/cm2 (n = 18) in female. Z-score of most HME patients show < 0, indicating that these patients tend to have low bone mass compared with the age-matched population. According to the T-score of BMD, 30% (6 of 20) and 67.5% (27 of 40) of the patients fell in the range of osteopenia in the lumbar spine and femoral neck areas, respectively. Serum osteocalcin and urinary NTx were in the normal range in most patients. There was no significant correlation between genotypes and Z-score. CONCLUSION HME patients have low bone mass, especially in the femoral neck area. They do not have abnormal bone metabolism, and there was no correlation between genotypes and Z-score.
Collapse
Affiliation(s)
- K Matsumoto
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, 1-1, Yanagido, Gifu, 501-1194, Japan.
| | - H Ogawa
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, 1-1, Yanagido, Gifu, 501-1194, Japan
| | - S Nozawa
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, 1-1, Yanagido, Gifu, 501-1194, Japan
| | - H Akiyama
- Department of Orthopaedic Surgery, Gifu University, Graduate School of Medicine, 1-1, Yanagido, Gifu, 501-1194, Japan
| |
Collapse
|
|
45
|
Matsumoto K, Ogawa H, Akiyama H. Radiographic characteristics of the hip joint in skeletally mature patients with multiple hereditary exostoses. Skeletal Radiol 2020; 49:1773-1779. [PMID: 32474654 DOI: 10.1007/s00256-020-03482-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/13/2020] [Accepted: 05/21/2020] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To elucidate the radiological characteristics of the hips, especially in proximal femur, of skeletally mature patients with multiple hereditary exostoses (MHE). MATERIALS AND METHODS Fifty eligible patients (100 hips) were included in the study and assigned to the MHE group. The control group included age- and sex-matched individuals, and the radiographs of 100 hips were used as controls. We examined the anatomical characteristics of the acetabulum and the proximal femur, including the acetabular depth-width ratio (ADR), Sharp's angle, femoral neck-shaft angle (NSA), Wiberg's centre-edge angle (CEA), femoral neck axis length (FNAL), femoral head diameter, (FHD), femoral neck width (FNW), femoral shaft width (FSW), femoral neck-shaft angle (NSA), and femoral head-neck ratio (FHNR = FHD/FNW). p value < 0.05 was considered significant. RESULTS Osteochondroma was frequently observed in the medial femoral neck (79%), but it was rarely found in the femoral head (1%). ADR and Sharp's angle were not significantly different between the MHE and control groups (p = 0.2056, p = 0.5025). CEA was significantly different between the two groups (p < 0.0001). FNW was significantly larger in the MHE group than in the control group (p < 0.0001). FHNR was significantly different between the two groups (p < 0.0001). NSA was significantly larger than the MHE group (141.8° ± 9.7° vs 129.5° ± 5.6°, p < 0.0001). CONCLUSIONS Hip dysplasia in the pelvic side was not commonly observed in skeletally mature MHE patients. However, they showed femoral neck widening and coxa valga. The occurrence of osteochondroma around the femoral neck affects the degree of valgus deformity. These facts could be useful for orthopaedic surgeons treating MHE patients.
Collapse
Affiliation(s)
- Kazu Matsumoto
- Department of Orthopaedic Surgery, Graduate School of Medicine, Gifu University, 1-1, Yanagido, Gifu, 501-1194, Japan.
| | - Hiroyasu Ogawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Gifu University, 1-1, Yanagido, Gifu, 501-1194, Japan
| | - Haruhiko Akiyama
- Department of Orthopaedic Surgery, Graduate School of Medicine, Gifu University, 1-1, Yanagido, Gifu, 501-1194, Japan
| |
Collapse
|
|
46
|
Chen Z, Ruan W, Li M, Cao L, Lu J, Zhong F, Bi Q. A Novel Nonsense Mutation in the EXT2 Gene Identified in a Family with Hereditary Multiple Osteochondromas. Genet Test Mol Biomarkers 2020; 24:478-483. [PMID: 32678989 DOI: 10.1089/gtmb.2020.0017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Zhonghua Chen
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, P.R. China
| | - Weiwei Ruan
- Department of Orthopedics, Tongde Hospital of Zhejiang Provincial, Hangzhou, P.R. China
| | - Menglu Li
- Institute of Cancer Research and Basic Medical Sciences, Cancer Hospital of University Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, P.R. China
| | - Li Cao
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, P.R. China
| | - Jianwei Lu
- Department of Orthopedics, Tongde Hospital of Zhejiang Provincial, Hangzhou, P.R. China
| | - Fuhua Zhong
- Department of Orthopedics, Tongde Hospital of Zhejiang Provincial, Hangzhou, P.R. China
| | - Qing Bi
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, P.R. China
| |
Collapse
|
|
47
|
Severmann AC, Jochmann K, Feller K, Bachvarova V, Piombo V, Stange R, Holzer T, Brachvogel B, Esko J, Pap T, Hoffmann D, Vortkamp A. An altered heparan sulfate structure in the articular cartilage protects against osteoarthritis. Osteoarthritis Cartilage 2020; 28:977-987. [PMID: 32315715 PMCID: PMC8422443 DOI: 10.1016/j.joca.2020.04.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 04/05/2020] [Accepted: 04/09/2020] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Osteoarthritis (OA) is a progressive degenerative disease of the articular cartilage caused by an unbalanced activity of proteases, cytokines and other secreted proteins. Since heparan sulfate (HS) determines the activity of many extracellular factors, we investigated its role in OA progression. METHODS To analyze the role of the HS level, OA was induced by anterior cruciate ligament transection (ACLT) in transgenic mice carrying a loss-of-function allele of Ext1 in clones of chondrocytes (Col2-rtTA-Cre;Ext1e2fl/e2fl). To study the impact of the HS sulfation pattern, OA was surgically induced in mice with a heterozygous (Ndst1+/-) or chondrocyte-specific (Col2-Cre;Ndst1fl/fl) loss-of-function allele of the sulfotransferase Ndst1. OA progression was evaluated using the OARSI scoring system. To investigate expression and activity of cartilage degrading proteases, femoral head explants of Ndst1+/- mutants were analyzed by qRT-PCR, Western Blot and gelatin zymography. RESULTS All investigated mouse strains showed reduced OA scores (Col2-rtTA-Cre;Ext1e2fl/e2fl: 0.83; 95% HDI 0.72-0.96; Ndst1+/-: 0.83, 95% HDI 0.74-0.9; Col2-Cre;Ndst1fl/fl: 0.87, 95% HDI 0.76-1). Using cartilage explant cultures of Ndst1 animals, we detected higher amounts of aggrecan degradation products in wildtype samples (NITEGE 4.24-fold, 95% HDI 1.05-18.55; VDIPEN 1.54-fold, 95% HDI 1.54-2.34). Accordingly, gelatin zymography revealed lower Mmp2 activity in mutant samples upon RA-treatment (0.77-fold, 95% HDI: 0.60-0.96). As expression of major proteases and their inhibitors was not altered, HS seems to regulate cartilage degeneration by affecting protease activity. CONCLUSION A decreased HS content or a reduced sulfation level protect against OA progression by regulating protease activity rather than expression.
Collapse
Affiliation(s)
- A-C Severmann
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - K Jochmann
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - K Feller
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - V Bachvarova
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - V Piombo
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - R Stange
- Zentrum für Muskuloskelettale Medizin, Westfälische Wilhelms-Universität Münster, Germany.
| | - T Holzer
- Center for Biochemistry, Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Medical Faculty, University of Cologne, Germany.
| | - B Brachvogel
- Center for Biochemistry, Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Medical Faculty, University of Cologne, Germany.
| | - J Esko
- Department of Cellular and Molecular Medicine, Glycobiology Research & Training Center, University of California, San Diego, La Jolla, CA, 92093-0687, USA.
| | - T Pap
- Zentrum für Muskuloskelettale Medizin, Westfälische Wilhelms-Universität Münster, Germany.
| | - D Hoffmann
- Department Bioinformatics and Computational Biophysics, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| | - A Vortkamp
- Department of Developmental Biology, Center for Medical Biotechnology, Faculty Biology, University Duisburg-Essen, Germany.
| |
Collapse
|
|
48
|
Liang C, Wang YJ, Wei YX, Dong Y, Zhang ZC. Identification of Novel EXT Mutations in Patients with Hereditary Multiple Exostoses Using Whole-Exome Sequencing. Orthop Surg 2020; 12:990-996. [PMID: 32293802 PMCID: PMC7307237 DOI: 10.1111/os.12660] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/11/2020] [Accepted: 02/19/2020] [Indexed: 12/16/2022] Open
Abstract
Objective To find novel potential gene mutations other than EXT1 and EXT2 mutations, to expand the mutational spectrum of EXT and to explore the correlation between clinical outcome and genotype in patients with hereditary multiple exostoses (HME). Methods The study recruited seven families diagnosed with multiple osteochondromas (MO). Family histories and clinical information were collected in detail through comprehensive physical and image examination. Patients with deformities and functional limitations were classified as “severe” and the remaining without functional limitations were classified as “mild,” in accordance with previous study. Whole‐exome sequencing (WES) was performed on a total of 13 affected individuals, 1 available unaffected relative, and 10 healthy unrelated individuals. Sanger sequencing was used to validate the screened mutations. Finally, the structural change in protein caused by pathogenic mutations was analyzed using information from the relevant database online and we attempted to correlate clinical phenotype with genotype in patients with HME. Results Other than EXT1 and EXT2, no novel potential gene mutations were found through WES. We identified nine heterozygous mutations in EXT1 or EXT2. Of these mutations, four have not been reported previously. These are c.996delT in exon 2 of EXT1 (family 1), c.544C > T in exon 3 of EXT2 (family 2), c.1171C > T in exon 7 of EXT2 (family 5), and c.823–824delAA in exon 5 of EXT1 (family 7). The other five mutations have already been reported in previous works. It was surprising that we found two mutation sites, in exon 2 and exon 5, respectively, of EXT1 in 1 patient diagnosed with MO, when his father had two mutation sites, in exon 6 and exon 5, respectively, of EXT1 and EXT2 (family 4). In addition, 1 patient showed degeneration, while his father only exhibited slight symptoms (family 7). In our study, among 51 affected patients in seven families, the sex ratio (male vs female) was 58.9% (n = 30) vs 41.2% (n = 21). Male patients seemed to show more severe symptoms compared to females, but because the sample was small, we did not obtain statistically significance results. Conclusion Whole‐exome sequencing to screen pathogenic gene mutations was applied successfully. Although no third‐gene mutation associated with HME was found, a total of nine mutations across EXT1 and EXT2 were identified, four of which are novel. Our results expand the mutational spectrum of EXT and can be used in genetic counseling and prenatal diagnosis for patients with MO.
Collapse
Affiliation(s)
- Chao Liang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yong-Jie Wang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yu-Xuan Wei
- Department of Orthopaedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Sciences and Peking Union Medical College, Shenzhen, China
| | - Yang Dong
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Zhi-Chang Zhang
- Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| |
Collapse
|
|
49
|
Fusco C, Nardella G, Fischetto R, Copetti M, Petracca A, Annunziata F, Augello B, D'Asdia MC, Petrucci S, Mattina T, Rella A, Cassina M, Bengala M, Biagini T, Causio FA, Caldarini C, Brancati F, De Luca A, Guarnieri V, Micale L, D'Agruma L, Castori M. Mutational spectrum and clinical signatures in 114 families with hereditary multiple osteochondromas: insights into molecular properties of selected exostosin variants. Hum Mol Genet 2020; 28:2133-2142. [PMID: 30806661 DOI: 10.1093/hmg/ddz046] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 02/22/2019] [Accepted: 02/22/2019] [Indexed: 01/05/2023] Open
Abstract
Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or multiplex ligation-dependent probe amplification and qPCR. Eighty-seven disease-causative variants (55 novel and 32 known) were identified including frameshift (42%), nonsense (32%), missense (11%), splicing (10%) variants and genomic rearrangements (5%). Informative clinical features were available for 42 EXT1 and 27 EXT2 subjects. Osteochondromas were more frequent in EXT1 as compared to EXT2 patients. Anatomical distribution of lesions showed significant differences based on causative gene. Microscopy analysis for selected EXT1 and EXT2 variants verified that EXT1 and EXT2 mutants failed to co-localize each other and loss Golgi localization by surrounding the nucleus and/or assuming a diffuse intracellular distribution. In a cell viability study, cells expressing EXT1 and EXT2 mutants proliferated more slowly than cells expressing wild-type proteins. This confirms the physiological relevance of EXT1 and EXT2 Golgi co-localization and the key role of these proteins in the cell cycle. Taken together, our data expand genotype-phenotype correlations, offer further insights in the pathogenesis of HMO and open the path to future therapies.
Collapse
Affiliation(s)
- Carmela Fusco
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Grazia Nardella
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.,Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Rita Fischetto
- Unit of Metabolic Diseases and Medical Genetics, University Hospital, P.O. Giovanni XXIII Hospital, Bari, Italy
| | - Massimiliano Copetti
- Unit of Biostatistics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Antonio Petracca
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Francesca Annunziata
- Unit of Molecular Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Bartolomeo Augello
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Maria Cecilia D'Asdia
- Unit of Molecular Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Simona Petrucci
- Unit of Molecular Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.,Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Teresa Mattina
- Unit of Medical Genetics, University of Catania, Catania, Italy
| | - Annalisa Rella
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Matteo Cassina
- Unit of Clinical Genetics, Department of Women's and Children's Health, University of Padua, Padua, Italy
| | - Mario Bengala
- Dipartimento di Oncoematologia, U.O.C Laboratorio di Genetica Medica, Fondazione Policlinico di Tor Vergata, Rome, Italy
| | - Tommaso Biagini
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Francesco Andrea Causio
- Unit of Metabolic Diseases and Medical Genetics, University Hospital, P.O. Giovanni XXIII Hospital, Bari, Italy
| | - Camilla Caldarini
- Division of Orthopedics and Traumatology, Azienda Socio Sanitaria Territoriale Gaetano Pini, Milan, Italy
| | - Francesco Brancati
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.,Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI) IRCCS, Rome, Italy
| | - Alessandro De Luca
- Unit of Molecular Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Vito Guarnieri
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Lucia Micale
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Leonardo D'Agruma
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Marco Castori
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| |
Collapse
|
|
50
|
Abstract
Glycosylation refers to the covalent attachment of sugar residues to a protein or lipid, and the biological importance of this modification has been widely recognized. While glycosylation in mammals is being extensively investigated, lower level animals such as invertebrates have not been adequately interrogated for their glycosylation. The rich diversity of invertebrate species, the increased database of sequenced invertebrate genomes and the time and cost efficiency of raising and experimenting on these species have enabled a handful of the species to become excellent model organisms, which have been successfully used as tools for probing various biologically interesting problems. Investigation on invertebrate glycosylation, especially on model organisms, not only expands the structural and functional knowledgebase, but also can facilitate deeper understanding on the biological functions of glycosylation in higher organisms. Here, we reviewed the research advances in invertebrate glycosylation, including N- and O-glycosylation, glycosphingolipids and glycosaminoglycans. The aspects of glycan biosynthesis, structures and functions are discussed, with a focus on the model organisms Drosophila and Caenorhabditis. Analytical strategies for the glycans and glycoconjugates are also summarized.
Collapse
Affiliation(s)
- Feifei Zhu
- 1 Institute of Life Sciences, Jiangsu University , Zhenjiang 212013 , People's Republic of China.,2 School of Food and Biological Engineering, Jiangsu University , Zhenjiang 212013 , People's Republic of China
| | - Dong Li
- 1 Institute of Life Sciences, Jiangsu University , Zhenjiang 212013 , People's Republic of China
| | - Keping Chen
- 1 Institute of Life Sciences, Jiangsu University , Zhenjiang 212013 , People's Republic of China
| |
Collapse
|