ED-71 ameliorates bone regeneration in type 2 diabetes by reducing ferroptosis in osteoblasts via the HIF1α pathway

Eldecalcitol (ED-71), a novel active form of vitamin D, shows potential in treating osteoporosis. However, its underlying mechanisms of action remain to be determined. This study aimed to investigate the effect of ED-71 on bone regeneration and to illustrate its mode of action. The in-vitro model was developed using rat primary osteoblasts cultured under high-glucose conditions, and these cells were treated with ED-71. Additionally, an in vivo model of cranial bone defects was established in type 2 diabetic rats, and ED-71 was administered by gavage. The results demonstrated that ED-71 prevented osteoblast cell death, enhanced rat primary osteoblasts' osteogenic capacity, and attenuated the overexpression of hypoxia-inducible factor 1α (HIF1α) induced by high glucose levels. Furthermore, ED-71 increased glutathione peroxidase 4 (GPX4) levels and inhibited ferroptosis in response to hyperglycemic stimulation. Notably, interference with the HIF1α activator and ferroptosis activator Erastin significantly reduced the therapeutic effects of edetate osteolysis. These findings were further tested in vivo experiments. These results suggest that ED-71 activates the HIF1α pathway in vivo and in vitro, effectively relieving the ferroptosis induced by high glucose. Significantly, ED-71 may improve osteogenic disorders caused by diabetes.