Tristetraprolin protects against osteoarthritis by restraining chondrocyte mitochondrial DNA release through...

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.

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.

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 Arctium lappa, was identified as a TTP-dependent pharmacological activator that suppressed CMPK2 expression and mitigated OA progression in vivo.

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.

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.