Cyclic tensile stress restores chondrocyte homeostasis via integrin-FAK-RhoA/ROCK2 signaling: A multi-omics study

The disruption of chondrocyte homeostasis, manifesting as an anabolic/catabolic imbalance and increased apoptosis, is a hallmark of osteoarthritis (OA). While physiological mechanical stimuli are protective, the molecular mechanisms rescuing degenerative chondrocytes remain unclear. This study elucidates how cyclic tensile stress (TS) restores homeostasis using primary chondrocytes from rats with anterior cruciate ligament transection-induced OA. These degenerative chondrocytes exhibited suppressed anabolism (Acan, Col2a1 downregulation) and elevated catabolism (Mmp13, Adamts5 upregulation). Application of TS (10% strain, 0.5 Hz) significantly reversed this pathogenic phenotype, restoring cell viability and extracellular matrix synthesis. Integrated transcriptomic and proteomic analyses identified "Focal Adhesion" as the most significantly enriched pathway. Mechanistically, TS reactivated the suppressed Integrin-FAK-RhoA/ROCK2 cascade, evidenced by increased FAK phosphorylation (Y397) and RhoA/ROCK2 expression. Crucially, FAK knockdown abolished the TS-induced upregulation of RhoA and ROCK2, confirming FAK as the essential mediator. These findings demonstrate that TS rescues degenerative chondrocytes by reactivating the Integrin-FAK-RhoA/ROCK2 axis, suggesting a potential mechanobiological therapeutic target for OA.