With the prevalence of coronavirus disease 2019, the administration of glucocorticoids (GCs) has become more widespread. Treatment with high‐dose GCs leads to a variety of problems, of which steroid‐induced osteonecrosis of the femoral head (SONFH) is the most concerning. Since hypoxia‐inducible factor 1α (HIF‐1α) is a key factor in cartilage development and homeostasis, it may play an important role in the development of SONFH. In this study, SONFH models were established using methylprednisolone (MPS) in mouse and its proliferating chondrocytes to investigate the role of HIF‐1α in cartilage differentiation, extracellular matrix (ECM) homeostasis, apoptosis and glycolysis in SONFH mice. The results showed that MPS successfully induced SONFH in vivo and vitro, and MPS‐treated cartilage and chondrocytes demonstrated disturbed ECM homeostasis, significantly increased chondrocyte apoptosis rate and glycolysis level. However, compared with normal mice, not only the expression of genes related to collagens and glycolysis, but also chondrocyte apoptosis did not demonstrate significant differences in mice co‐treated with MPS and HIF‐1α inhibitor. And the effects observed in HIF‐1α activator‐treated chondrocytes were similar to those induced by MPS. And HIF‐1α degraded collagens in cartilage by upregulating its downstream target genes matrix metalloproteinases. The results of activator/inhibitor of endoplasmic reticulum stress (ERS) pathway revealed that the high apoptosis rate induced by MPS was related to the ERS pathway, which was also affected by HIF‐1α. Furthermore, HIF‐1α affected glucose metabolism in cartilage by increasing the expression of glycolysis‐related genes. In conclusion, HIF‐1α plays a vital role in the pathogenesis of SONFH by regulating ECM homeostasis, chondrocyte apoptosis, and glycolysis.

中文翻译：

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HIF-1α 在类固醇诱导股骨头坏死小鼠软骨稳态、细胞凋亡和糖酵解中的作用

随着 2019 年冠状病毒病的流行，糖皮质激素 (GC) 的使用变得更加普遍。高剂量GC治疗会导致多种问题，其中最令人担忧的是类固醇引起的股骨头坏死（SONFH）。由于缺氧诱导因子 1α (HIF-1α) 是软骨发育和稳态的关键因素，因此它可能在 SONFH 的发生发展中发挥重要作用。本研究利用甲基强的松龙（MPS）在小鼠及其增殖软骨细胞中建立 SONFH 模型，以研究 HIF-1α 在 SONFH 小鼠软骨分化、细胞外基质（ECM）稳态、细胞凋亡和糖酵解中的作用。结果表明，MPS 在体内和体外成功诱导 SONFH，并且 MPS 处理的软骨和软骨细胞表现出 ECM 稳态紊乱，显着增加软骨细胞凋亡率和糖酵解水平。然而，与正常小鼠相比，MPS和HIF-1α抑制剂联合治疗的小鼠不仅胶原蛋白和糖酵解相关基因的表达，而且软骨细胞凋亡也没有表现出显着差异。在 HIF-1α 激活剂处理的软骨细胞中观察到的效果与 MPS 诱导的效果相似。HIF-1α 通过上调其下游靶基因基质金属蛋白酶来降解软骨中的胶原蛋白。内质网应激（ERS）通路激活剂/抑制剂结果显示，MPS诱导的高细胞凋亡率与ERS通路有关，而ERS通路也受到HIF-1α的影响。此外，HIF-1α通过增加糖酵解相关基因的表达来影响软骨中的葡萄糖代谢。总之，HIF-1α通过调节ECM稳态、软骨细胞凋亡和糖酵解在SONFH的发病机制中发挥着至关重要的作用。