β-Ecdysone attenuates cartilage damage in a mouse model of collagenase-induced osteoarthritis via mediating FOXO1/ADAMTS-4/5 signaling axis.

Background: β-Ecdysone has been reported to perform a protective effect to prevent interleukin 1β (IL-1β)-induced apoptosis and inflammatory response in chondrocytes. In our study, the chondroprotective effects of β-Ecdysone were explored in a mouse model of collagenase-induced osteoarthritis (OA).

Methods: Injection of collagenase in the left knee was implemented to establish a mouse model of OA. The histomorphological analysis was detected using safranine O staining. Serum pro-inflammatory cytokines were measured by ELISA assays. Protein expression in the femur and chondrocytes was analyzed using western blot. Chondrocyte apoptosis was evaluated by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining.

Results: Treatment of OA mice with β-Ecdysone supplementation significantly inhibited the production of pro-inflammatory cytokines. Histologic examination exhibited that the degradation of proteoglycans and the loss of trabecular bone were observed in collagenase-injected mice. However, OA-like changes were attenuated by β-Ecdysone administration in collagenase-injected mice. Both in vivo and in vitro models, nuclear forkhead box O1 (FOXO1) protein expression was significantly reduced in the femur of collagenase-treated mice and IL-1β-stimulated chondrocytes. However, β-Ecdysone treatment was able to rescue FOXO1 protein expression in the nucleus to inhibit the transcription and translation of a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 4 (ADAMTS-4) and ADAMTS-5.

Conclusion: The findings suggested that β-Ecdysone functioned as a FOXO1 activator to protect collagenase-induced cartilage damage. FOXO1 might be a potential molecular target of β-Ecdysone for the effective prevention and treatment of OA.