Mechanical stress promotes synovial inflammation and osteoarthritis development via the NF-κB p52/IL-6 signalling pathway.

Abstract

OBJECTIVES: TM joint OA (TMJOA) is a multifactorial degenerative disorder involving biomechanical and inflammatory processes. Yet, how mechanical stress causes synovial inflammation and cartilage degradation is unclear. This study aimed to explore the relationship between mechanical stress and inflammatory responses in TMJOA. METHODS: SF cytokine profiles from TMJOA patients and controls were analysed using high-throughput antibody microarrays and validated by ELISA. Finite element analysis (FEA) was employed to map mechanical stress distributions in the mandibular condyle post-surgery. A unilateral anterior crossbite rats model was established to mimic mechanical stress-induced OA, with subsequent evaluation of cartilage degeneration and synovial IL-6 expression. RNA sequencing was employed to identify mechanosensitive genes regulating IL-6/IL-8 induction, followed by in vitro validation of signalling pathway using primary synovial fibroblasts and chondrocytes. RESULTS: Synovial IL-6 and IL-8 levels were significantly elevated in TMJOA patients post-mandibular advancement surgery compared with those with TM joint disc displacement. ELISA confirmed these findings, demonstrating a strong positive correlation between IL-6 levels and both joint pain score and reduced maximum mouth opening. FEA revealed uneven mechanical stress redistribution in the condyle post-surgery, with IL-6 levels correlating with mandibular advancement distance. In a murine model of mechanical stress-induced OA, cartilage exhibited OA-like degenerative changes accompanied by elevated synovial IL-6 levels. Mechanistically, mechanical loading induced IL-6 via integrin αIIbβ3 activation, triggering non-canonical nuclear factor (NF)-κB signalling. CONCLUSION: Mechanical stress drives TMJOA synovial inflammation via integrin αIIbβ3/NF-κB-mediated IL-6 secretion, linking biomechanical perturbations to cartilage degradation. Targeting this pathway may offer novel therapeutic strategies for TMJOA.