Conclusions
D-mannose alleviates osteoarthritis progression by suppressing HIF-2α-mediated chondrocyte sensitivity to ferroptosis, indicating D-mannose to be a potential therapeutic strategy for ferroptosis-related diseases.
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-1β (IL-1β) 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 α) 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-2α was identified as a central mediator in D-mannose-induced ferroptosis resistance of chondrocytes. Furthermore, overexpression of HIF-2α 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-2α-mediated chondrocyte sensitivity to ferroptosis, indicating D-mannose to be a potential therapeutic strategy for ferroptosis-related diseases.