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.

HIF-1α in Osteoarthritis: From Pathogenesis to Therapeutic Implications

“…Targeting the mitophagy pathway in marrow mesenchymal stem cells may improve their survival capacity and chondrogenic differentiation for cell-based therapies in OA ( Sun et al, 2021 ). Overexpression of HIF-1α, through its downstream marker BNIP3, increases mitophagy induced by hypoxia and protects bone cells from apoptosis ( Xu et al, 2021 ). By enhancing BNIP3 expression, HIF-1α could alleviate hypoxia-induced apoptosis, senescence and matrix degradation in chondrocytes through mitophagy ( Hu et al, 2020b ).…”

Zuo-Gui-Wan Aqueous Extract Ameliorates Glucocorticoid-Induced Spinal Osteoporosis of Rats by Regulating let-7f and Autophagy

“…In addition, activation of autophagy by Beclin-1 overexpression induced osteoclast differentiation and conditional ablation of ATG7 and treatment with chloroquine, an autophagy inhibitor, ameliorated GC-induced bone loss via inhibiting osteoclastogenesis ( 18 ). Besides, recent studies indicated that GC can induce bone fragility and reduce osteocyte numbers by suppressing autophagy ( 19 ). Therefore, the maladjustment of autophagy may have a relationship with the occurrence and progression of GIOP, but related studies are still insufficient.…”

Network-Based Pharmacology and Bioinformatics Study on the Mechanism of Action of Gujiansan in the Treatment of Steroid-Induced Avascular Necrosis of the Femoral Head

“…HIF-1 α expression was decreased in the necrotic bone tissue of SANFH, and HIF-1 α compensatory expression was upregulated in early bone tissue under hypoxic or anoxic conditions. However, with the progression of the disease, the imbalance of energy metabolism in necrotic bone tissue was aggravated, and the expression levels of HIF-1 α , VEGF, HMOX1, and BNIP3 were decreased, resulting in the decreased differentiation and apoptosis of vascular endothelial cells [ 53 , 54 ]. (4) For the AGE-RAGE signaling pathway, under the action of GC, advanced glycation end products (AGE) and ROS accumulation occur in bone tissues and blood vessels of necrotic bone regions [ 55 ].…”