Conclusion
Prophylactic treatment with Resatorvid alleviates TMJOA pathology by inhibiting chondrocyte pyroptosis and degeneration, as well as ROS-induced macrophage inflammation, through TLR4/MyD88/NF-κB/NLRP3.
Methods
An intra-articular injection of complete Freund's adjuvant (CFA) was used to induce an experimental inflammatory mouse TMJOA model, and TLR4 expression was identified by immunofluorescent labeling. Intraperitoneal injections of Resatorvid were administered to CFA-induced TMJOA mice, and the pathology of TMJOA animals with and without Resatorvid treatment was examined by H&E, Safranin-O/Fast Green, and TRAP staining, as well as micro-CT, immunohistochemistry, and immunofluorescence. The impact of Resatorvid on chondrocyte pyroptosis and macrophage inflammation was further investigated using ATDC5 chondrocytes and RAW264.7 macrophages pretreated with relevant antagonists.
Results
CFA-induced TMJOA mice revealed remarkable synovial inflammation, together with a time course of cartilage degradation and bone destruction, with TLR4 elevated in the synovium and condylar cartilage. Prophylactic treatment with Resatorvid mitigated synovial inflammation, cartilage degeneration, and bone destruction in CFA-induced TMJOA mice and downregulated MyD88/NF-κB expression. Ex vivo studies demonstrated that Resatorvid treatment alleviated NOD-like receptor protein 3 (NLRP3)-mediated chondrocyte pyroptosis and degeneration and relieved macrophage inflammation by preventing reactive oxygen species (ROS) production through NLRP3 signaling.