title: Matrix cross-linking-mediated mechanotransduction promotes posttraumatic osteoarthritis.
abstract: Osteoarthritis (OA) is characterized by impairment of the load-bearing function of articular cartilage. OA cartilage matrix undergoes extensive biophysical remodeling characterized by decreased compliance. In this study, we elucidate the mechanistic origin of matrix remodeling and the downstream mechanotransduction pathway and further demonstrate an active role of this mechanism in OA pathogenesis. Aging and mechanical stress, the two major risk factors of OA, promote cartilage matrix stiffening through the accumulation of advanced glycation end-products and up-regulation of the collagen cross-linking enzyme lysyl oxidase, respectively. Increasing matrix stiffness substantially disrupts the homeostatic balance between chondrocyte catabolism and anabolism via the Rho-Rho kinase-myosin light chain axis, consequently eliciting OA pathogenesis in mice. Experimental enhancement of nonenzymatic or enzymatic matrix cross-linking augments surgically induced OA pathogenesis in mice, and suppressing these events effectively inhibits OA with concomitant modulation of matrix degrading enzymes. Based on these findings, we propose a central role of matrix-mediated mechanotransduction in OA pathogenesis.
authors.affiliation: School of Life Sciences, Cell Dynamics and Integrative Aging Research Centers, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea; Department of Biological Sciences, Seoul National University, Seoul 151-747, Korea;
authors.forename: Jin-Hong
authors.initials: JH
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Cell Dynamics and Integrative Aging Research Centers, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
authors.forename: Gyuseok
authors.initials: G
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Cell Dynamics and Integrative Aging Research Centers, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
authors.forename: Yoonkyung
authors.initials: Y
authors.lastname: Won
authors.affiliation: School of Life Sciences, Cell Dynamics and Integrative Aging Research Centers, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
authors.forename: Minju
authors.initials: M
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Cell Dynamics and Integrative Aging Research Centers, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea;
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Kwak
authors.affiliation: Department of Orthopedic Surgery, Wonkwang University School of Medicine, Iksan 570-711, Korea.
authors.forename: Churl-Hong
authors.initials: CH
authors.lastname: Chun
authors.affiliation: School of Life Sciences, Cell Dynamics and Integrative Aging Research Centers, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea; jschun@gist.ac.kr.
authors.forename: Jang-Soo
authors.initials: JS
authors.lastname: Chun
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000368:Aged; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002358:Cartilage, Articular / Q000473:pathology*; D019902:Chondrocytes / Q000166:cytology; D003094:Collagen / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D017930:Genes, Reporter; D017127:Glycation End Products, Advanced / Q000737:chemistry; D006801:Humans; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D010003:Osteoarthritis / Q000473:pathology*; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D013314:Stress, Mechanical; D000099166:Polyacrylamides; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000180:Acrylic Resins; D051792:Basic Helix-Loop-Helix Proteins; D003094:Collagen; D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced; D008249:Protein-Lysine 6-Oxidase; D000099166:Polyacrylamides; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: cartilage; lysyl oxidase; matrix stiffness; mechanotransduction; osteoarthritis