Tristetraprolin protects against osteoarthritis by restraining chondrocyte mitochondrial DNA release through post-transcriptional regulation.

Background and objective: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and chronic inflammation. Tristetraprolin (TTP) is an RNA-binding protein with anti-inflammatory properties, but its role in OA remains unclear. This study aimed to investigate the function of TTP in chondrocytes and elucidate its mechanism in protecting against OA. Methods: TTP expression was assessed in human OA cartilage and IL-1β-treated chondrocytes using immunohistochemistry and western blotting. Functional studies were performed in primary chondrocytes and cartilage explants using siRNA-mediated knockdown or plasmid-mediated overexpression of TTP. In vivo, chondrocyte-specific TTP knockout and overexpression models were established in mice. RNA-sequencing, RNA immunoprecipitation, mRNA decay assays, and luciferase reporter assays were performed to identify and validate TTP targets. The role of the identified target, CMPK2, and its downstream cGAS/STING/NF-κB pathway was investigated both in vitro and in vivo. Finally, the therapeutic potential of arctigenin, a TTP-activating natural compound, was evaluated in OA model mice. Results: TTP expression was significantly downregulated in OA cartilage. TTP deficiency exacerbated OA pathology, while its overexpression protected against cartilage degeneration. Mechanistically, TTP was found to bind directly to the 3'-UTR of CMPK2 mRNA, promoting its degradation. This, in turn, reduced the release of mtDNA into the chondrocyte cytoplasm and suppressed the activation of the cGAS/STING/NF-κB signaling pathway. Furthermore, arctigenin, a natural compound from Conclusion: TTP protects chondrocytes against OA by restraining CMPK2-mediated mtDNA cytoplasm release and suppressing cGAS/STING/NF-κB signaling. Arctigenin exerts its chondroprotective effects in a TTP-dependent manner and represents a promising therapeutic candidate for OA. The translational potential of this article: This study identifies a novel TTP-CMPK2-mtDNA-cGAS/STING/NF-κB signaling axis in chondrocytes, revealing a mechanistic pathway that contributes to OA pathogenesis. By demonstrating that arctigenin can activate TTP to suppress cartilage degeneration, these findings highlight a potential therapeutic strategy for OA. Targeting post-transcriptional regulation via TTP may inform the development of novel disease-modifying interventions, supporting translational applications in OA treatment.