Matrix cross-linking–mediated mechanotransduction promotes posttraumatic osteoarthritis

Abstract

Osteoarthritis (OA) is characterized by impairment of the loadbearing 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. Various pathological conditions in human diseases are associated with aberrant ECM remodeling and consequent deviation from intrinsic ECM material properties (2). Mechanical perturbation of ECM affects the ways in which cells respond to externally applied mechanical forces and generate internal traction forces through cell-matrix interactions (3). Therefore, elucidation of the functional relationships between ECM mechanics and cellular transduction pathways is of critical importance.Articular cartilage ECM consisting of a collagenous network and highly charged proteoglycans confers the unique load-bearing function to joints. The dense aggregates of negatively charged proteoglycans provide resistance to compressive loading by promoting osmotic swelling, which is counterbalanced by cross-linked collagen fibrils that confer tissue tensile strength. Disruption of this delicate balance leads to structural damage and functional failure of articular cartilage and, consequently, to development of osteoarthritis (OA), the most common arthropathy (4, 5). OA cartilage ECM undergoes extensive remodeling, characterized by a decrease in matrix compliance (6, 7). These changes occur at the level of individual collagen fibrils, although the precise mechanisms regulating matrix remodeling remain elusive. Notably, matrix remodeling precedes cartilage destruction (6, 7), suggesting that monitoring the mechanical properties of cartilage matrix could serve as an innovative diagnostic approach for early detection of OA. Significant influence of matrix stiffness on mesenchymal lineage specification has been documented, and data have been obtained on the optimal ranges of substrate rigidity promoting osteogenesis. This regulatory process requires nonmuscle myosin II activity, with concomitant effects on adhesion and actin cytoskeleton structures (8).I...

Mechanical confinement regulates cartilage matrix formation by chondrocytes

“…Previous studies proposed the role of either cartilage matrix stiffening 50 or volume expansion 43 in the initiation of osteoarthritis. We found that restricted cell expansion by a more elastic microenvironment induces IL-1β signaling.…”

Pro-inflammatory cytokines and structural biomarkers are effective to categorize osteoarthritis phenotype and progression in Standardbred racehorses over five years of racing career

“…Biochemical changes could affect the mechanical properties of HAC: lysyl-oxidase (LOX) pathway increases cross-linking in the collagen substrate and cartilage stiffness, LOX overexpression affects chondrocytes activation profiles of transcriptional factors, and among these the NF-kβ pathway, which is associated to the increased expression of matrix-degradative enzymes [42]. Modification in the pericellular matrix in HAC has a critical role in controlling the module of elasticity of the cartilage [43].…”

Ageing and the pathogenesis of osteoarthritis

“…Whether limiting AGE accumulation would be sufficient to prevent age-related OA remains unclear, but genetic deletion of lysyl oxidase (an enzymatic collagen crosslinker that is upregulated by joint injury) protected mice from injury-induced OA 104 . The potential relevance of this finding to AGEs and thus ageing was suggested by the finding that collagen crosslinking induced by AGEs and by lysyl oxidase had similar effects on chondrocyte signalling in collagen gels and on the development of OA after injury.…”

“…A mouse model of injury-induced OA demonstrated that collagen crosslinking occurs through a distinct mechanism involving lysyl oxidase 104 .…”