SOX9 attenuates osteoarthritis bNy regulating autophagy via the PI3K/Akt/mTOR pathway

The pathogenesis of osteoarthritis (OA) has remained unclear, posing a clinical challenge. Although SRY-box transcription factor 9 (SOX9) has been reported to inhibit OA progression, the specific mechanisms through which it regulates inflammation in OA, especially with respect to chondrocyte autophagy, remain poorly understood. In this study, we sought to elucidate the protective role of SOX9 in OA and its underlying mechanism. We found significantly reduced SOX9 expression in OA. In vitro, overexpression of SOX9 in chondrocytes significantly inhibited IL-1β-induced inflammation, whereas SOX9 knockdown in chondrocytes enhanced inflammation. Gene expression profiling revealed a strongly positive correlation of SOX9 with the expression of autophagy-related genes (Gabarapl2, r = 0.89; Ulk1, r = 0.69; Pten, r = 0.68). Additionally, SOX9-overexpression (SOX9-OE) restored IL-1β-induced autophagy inhibition, whereas SOX9-knockdown further suppressed chondrocyte autophagy. Rescue experiments showed that SOX9-OE reversed IL-1β-induced inflammatory response by enhancing the autophagic flux. Moreover, SOX9 regulated the expression of key genes in the PI3K/Akt/mTOR pathway. In vivo, intra-articular SOX9-OE enhanced the autophagy levels, suppressed inflammation, and alleviated cartilage damage, whereas its knockdown had opposite effects. This study is the first to establish the PI3K/Akt/mTOR-autophagy axis as the key mechanism through which SOX9 mitigates OA, providing new insights into OA pathogenesis and a potential therapeutic target for this prevalent joint disease.