Overexpression of HIF‐1α enhances the protective effect of mitophagy on steroid‐induced osteocytes apoptosis

Abstract Glucocorticoid (GC; dexamethasone, DEX) ‐induced osteonecrosis of the femoral head (GIOFH) is a challenging orthopedic disease, and its underlying mechanism remains not clear. This study exposed murine long bone osteocyte‐Y4 (MLO‐Y4) cells to DEX below normoxic or hypoxic circumstances and found that cell autophagy have been reduced. At the same time, flow cytometry analysis showed increased apoptosis, which was more pronounced in hypoxic environments. Recent research also claimed that GC induces osteoporosis after osteocyte apoptosis, and subsequent microfractures lead to ischemia and hypoxia of the femoral head, resulted in GIOFH. Presently, we found that both mitophagy‐related protein hypoxia‐inducible factor‐1α (HIF‐1α) and BNIP3 were up‐regulated in the hypoxic environment, and their expression was down‐regulated when exposed to DEX. Besides, we demonstrated that overexpressing HIF‐1α resisted DEX‐induced apoptosis in a hypoxic environment. Here, we demonstrated that overexpression of HIF‐1α, through its downstream marker BNIP3, reduced the suppression of DEX on mitophagy induced by hypoxia and protected bone cells from apoptosis. Also, these findings may provide a direction of the promising application for better GIOFH treatment shortly.