17‐β‐Estradiol Protects Chondrocytes From Senescence and Ameliorates Osteoarthritis Progression via ERα ‐ AKT ‐ FOXO4 Pathway

Osteoarthritis (OA) is a prevalent cause of joint pain in elderly individuals, and chondrocyte senescence plays a crucial role in its pathogenesis. FOXO4 has been identified as a crucial molecule in cellular senescence. However, little is known regarding its role in OA and the regulation of its expression. 17-β-Estradiol (E2) has been demonstrated to exert a protective effect in OA, yet the underlying mechanism remains largely unexplained. In this study, we reported a protective effect of E2 against multiple types of chondrocyte senescence, and this effect was mediated by oestrogen receptor α (ERα). Mechanically, E2 activated AKT and facilitated the nuclear export and the degradation of FOXO4, which played a crucial role in resisting senescence. Moreover, knockdown of FOXO4 in osteoarthritic chondrocytes alleviated cellular senescence. Furthermore, we demonstrated that intra-articular injection of E2 was effective in ameliorating surgery-induced OA in a rat model. Collectively, E2 contributed to the alleviation of chondrocyte senescence through the ERα-AKT-FOXO4 signalling pathway and ameliorated OA progression in the rat model. Our study offers a novel therapeutic approach for controlling chondrocyte senescence and provides insights into the role of E2 in treating OA.