TRAF3 modulates cartilage degradation through its suppression of interleukin 17 signaling.

: Interleukin 17A (IL-17A) plays critical role in the pathogenesis of autoimmune diseases through driving inflammatory cascades. However, the role of IL-17 in osteoarthritis (OA) is not well understood. TNF receptor associated factor 3 (TRAF3) is a receptor proximal negative regulator of IL-17 signaling. Whether TRAF3 exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of OA is not well understood. In this study, we found that TRAF3 notably suppressed IL-17-induced NF-κB and MAPK activation and subsequent the production of matrix-degrading enzymes. On the contrary, TRAF3 depletion enhanced IL-17 signaling, along with increased matrix-degrading enzymes production. In vivo, cartilage destruction caused by surgery-induced OA was markedly alleviated both in IL-17A deficient mice (IL17a-/-) and TRAF3 transgenic mice (T3TG). In contrast, silencing TRAF3 through adenoviruses worsened cartilage degradation in experimental OA. Moreover, the destructive effect of IL-17 on cartilage was abolished in T3TG mice in an IL-17 intra-articular (IA) injection animal model. Similarly, genetic deletion of IL-17 blocked TRAF3 knock down-mediated promotion of cartilage destruction, which suggests that the protective effect of TRAF3 on cartilage is mediated by its suppression of IL-17 signaling. Collectively, our results suggest that TRAF3 is critical in negative regulation of IL-17-mediated cartilage degradation and pathogenesis of OA, and may serve as a potential new therapy target for OA.