Exosomes mediate synovial-cartilage interaction and delay senescence via HMGB1/cGAS-STING pathway

Exosomes produced by synovial fibroblasts (SFB) have the capacity to penetrate articular cartilage, mediating interactions between the synovial membrane and cartilage, which is crucial for osteoarthritis (OA). The specific mechanisms by which SFB-derived exosomes influence OA-related chondrocytes remain unclear. In this study, we explored the impact of SFB-derived exosomes on chondrocyte senescence and assessed their role in cartilage degradation using a surgically induced rat model of OA. Utilizing a microarray-based approach, we confirmed that miR-126-3p levels were significantly reduced in synovial fluid exosomes from OA patients. Functionally, SFB-derived exosomes containing miR-126-3p were shown to prevent mitochondrial dysfunction and chondrocyte senescence. Our in vivo results demonstrated that exosomes enriched with SFB-derived miR-126-3p effectively hindered osteophyte formation, halted cartilage degradation, and exhibited anti-senescent effects on articular cartilage. Furthermore, we found that the HMGB1/cGAS-STING pathway played a key role in regulating chondrocyte senescence, and that exosomes carrying SFB-derived miR-126-3p mitigated chondrocyte senescence by suppressing HMGB1/cGAS-STING pathway. Collectively, our findings suggest that exosomes from SFB, delivering miR-126-3p to chondrocytes, can inhibit HMGB1/cGAS-STING signaling, thus reducing chondrocyte senescence and potentially alleviating the progression of OA.