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

FOXO4 expression is elevated in osteoarthritic chondrocytes and correlates with cellular senescence markers.

• FOXO4 was identified as a crucial molecule in cellular senescence in the context of OA.
• Knockdown of FOXO4 in osteoarthritic chondrocytes alleviated cellular senescence.
• FOXO4 was found to play a crucial role in resisting senescence when its nuclear export and degradation were facilitated.

17-β-Estradiol (E2) exerts a protective effect against multiple types of chondrocyte senescence.

• E2 was demonstrated to protect chondrocytes from multiple types of senescence.
• The protective effect of E2 against chondrocyte senescence was mediated by oestrogen receptor α (ERα).
• E2 contributed to the alleviation of chondrocyte senescence through the ERα-AKT-FOXO4 signalling pathway.

E2 activates AKT signalling to facilitate nuclear export and degradation of FOXO4 in chondrocytes.

• E2 activated AKT kinase in chondrocytes.
• AKT activation facilitated the nuclear export of FOXO4.
• AKT activation also promoted the degradation of FOXO4.
• This mechanistic pathway (ERα-AKT-FOXO4) represents the molecular basis by which E2 reduces chondrocyte senescence.

ERα mediates the protective effects of E2 on chondrocyte senescence.

• The protective effect of E2 against chondrocyte senescence was mediated by oestrogen receptor α (ERα).
• ERα was identified as the upstream receptor initiating the AKT-FOXO4 signalling cascade.
• The signalling pathway was described as ERα-AKT-FOXO4.

Intra-articular injection of E2 ameliorates surgery-induced osteoarthritis progression in a rat model.

• E2 was administered via intra-articular injection in the rat model.
• The OA model was surgery-induced in rats.
• Intra-articular injection of E2 was effective in ameliorating OA progression.
• The in vivo findings supported the in vitro mechanistic data on the ERα-AKT-FOXO4 pathway.

Chondrocyte senescence plays a crucial role in the pathogenesis of osteoarthritis, a prevalent cause of joint pain in elderly individuals.

• OA is described as a prevalent cause of joint pain in elderly individuals.
• Chondrocyte senescence was identified as a crucial factor in OA pathogenesis.
• FOXO4 was identified as a crucial molecule in cellular senescence relevant to OA.