Matrix cross-linking-mediated mechanotransduction promotes posttraumatic osteoarthritis.
Proc Natl Acad Sci U S A
; 112(30): 9424-9, 2015 Jul 28.
Article
em En
| MEDLINE
| ID: mdl-26170306
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Osteoartrite
/
Cartilagem Articular
/
Mecanotransdução Celular
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Aged
/
Animals
/
Humans
/
Male
/
Middle aged
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article