D-mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF-2α-dependent manner

Objectives Chondrocyte ferroptosis contributes to osteoarthritis (OA) progression, and D-mannose shows therapeutic value in many inflammatory conditions. Here, we investigated whether D-mannose interferes in chondrocyte ferroptotic cell death during osteoarthritic cartilage degeneration. Materials and methods In vivo anterior cruciate ligament transection (ACLT)-induced OA mouse model and an in vitro study of chondrocytes in an OA microenvironment induced by interleukin-1 beta (IL-1 beta) exposure were employed. Combined with Epas1 gene gain- and loss-of-function, histology, immunofluorescence, quantitative RT-PCR, Western blot, cell viability and flow cytometry experiments were performed to evaluate the chondroprotective effects of D-mannose in OA progression and the role of hypoxia-inducible factor 2 alpha (HIF-2 alpha) in D-mannose-induced ferroptosis resistance of chondrocytes. Results D-mannose exerted a chondroprotective effect by attenuating the sensitivity of chondrocytes to ferroptosis and alleviated OA progression. HIF-2 alpha was identified as a central mediator in D-mannose-induced ferroptosis resistance of chondrocytes. Furthermore, overexpression of HIF-2 alpha in chondrocytes by Ad-Epas1 intra-articular injection abolished the chondroprotective effect of D-mannose during OA progression and eliminated the role of D-mannose as a ferroptosis suppressor. Conclusions D-mannose alleviates osteoarthritis progression by suppressing HIF-2 alpha-mediated chondrocyte sensitivity to ferroptosis, indicating D-mannose to be a potential therapeutic strategy for ferroptosis-related diseases.