Deficient Mechanical Activation of Anabolic Transcripts and Post-Traumatic Cartilage Degeneration in Matrilin-1 Knockout Mice.
Matrilin-1 (Matn1), a cartilage-specific peri-cellular and extracellular matrix (ECM) protein, has been hypothesized to regulate ECM interactions and transmit mechanical signals in cartilage. Since Matn1 knock-out (Matn1-/-) mice exhibit a normal skeleton, its function in vivo is unclear. In this study, we found that the anabolic Acan and Col2a transcript levels were significantly higher in wildtype (Matn1+/+) mouse cartilage than that of MATN1-/- mice in vivo. However, such difference was not observed between Matn1+/+ and MATN1-/- chondrocytes cultured under stationary conditions in vitro. Cyclic loading significantly stimulated Acan and Col2a transcript levels in Matn1+/+ but not in MATN1-/- chondrocytes. This suggests that, while Matn1+/+ chondrocytes increase their anabolic gene expression in response to mechanical loading, the MATN1-/- chondrocytes fail to do so because of the deficiency in mechanotransduction. We also found that altered elastic modulus of cartilage matrix in Matn1-/- mice, suggesting the mechanotransduction has changed due to the deficiency of Matn1. To understand the impact of such deficiency on joint disease, mechanical loading was altered in vivo by destabilization of medial meniscus. While Matn1+/+ mice exhibited superficial fissures and clefts consistent with mechanical damage to the articular joint, Matn1-/- mice presented more severe cartilage lesions characterized by proteoglycan loss and disorganization of cells and ECM. This suggests that Matn1 deficiency affects pathogenesis of post-traumatic osteoarthritis by failing to up-regulate anabolic gene expression. This is the first demonstration of Matn1 function in vivo, which suggests its protective role in cartilage degeneration under altered mechanical environment.
Bone and Joint Research Center, The First Affiliated Hospital and Frontier Institute of Science and Technology, Xi'an JiaoTong University, Xi'an, 710061, China.|Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Yupeng
Y
Chen
Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Jack
J
Cossman
Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Chathuraka T
CT
Jayasuriya
Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Xin
X
Li
Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Yingjie
Y
Guan
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, 02912, United States of America.
Vera
V
Fonseca
Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Kun
K
Yang
Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Cherie
C
Charbonneau
Bone and Joint Research Center, The First Affiliated Hospital and Frontier Institute of Science and Technology, Xi'an JiaoTong University, Xi'an, 710061, China.|Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Hongchuan
H
Yu
Department of Orthopaedic Surgery, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.
Katsuaki
K
Kanbe
Department of Biologic and Materials Science, University of Michigan, Ann Arbor, Michigan, 48109, United States of America.
Peter
P
Ma
Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.|Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, 02912, United States of America.|Center for Biomedical Engineering, Brown University, Providence, RI, 02912, United States of America.
Eric
E
Darling
Bone and Joint Research Center, The First Affiliated Hospital and Frontier Institute of Science and Technology, Xi'an JiaoTong University, Xi'an, 710061, China.|Department of Orthopaedics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, United States of America.
Qian
Q
Chen
D053674:Aggrecans / Q000235:genetics*; D000818:Animals; D002357:Cartilage Diseases / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D064235:Matrilin Proteins / Q000235:genetics / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010003:Osteoarthritis / Q000209:etiology / Q000473:pathology; D014158:Transcription, Genetic
D053674:Aggrecans; D024043:Collagen Type II; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins