FKBP38 Alleviates Osteoarthritis Progression by Inhibiting Chondrocyte Senescence.

Abstract

ObjectiveOsteoarthritis (OA) is a prevalent age-related degenerative joint disease characterized by cartilage degeneration, joint pain, and reduced mobility, with aging as the primary risk factor. This study aimed to investigate the role and mechanism of FK506 binding protein 38 (FKBP38) in chondrocyte senescence and OA progression.MethodsFKBP38 expression was detected in articular cartilage from natural aging and OA mouse models. Mice with FKBP38 conditional knockout (FKBP38-cKO) and inducible conditional knockout (FKBP38-iKO) were generated for these models. An adeno-associated virus (AAV) vector overexpressing FKBP38 was injected into wild-type mouse joints. Joint damage was assessed at 8 and 18 months for natural aging or 4 and 8 weeks after DMM surgery by histology.ResultsFKBP38 expression was downregulated in cartilage from both natural aging and OA mice. FKBP38 overexpression protected against H2O2-induced senescence in chondrocytes. Addition of rapamycin to inhibit mTORC1 signaling rescued the enhanced senescence and catabolism caused by FKBP38 knockdown in chondrocytes. Conditional deletion of FKBP38 in chondrocytes significantly accelerated senescence and aggravated both natural aging and OA progression by activating mTORC1 signaling, whereas overexpression of FKBP38 delayed these processes.ConclusionThese results indicate that FKBP38 protects against chondrocyte senescence and cartilage degradation to alleviate OA progression by inhibiting mTORC1 signaling.