Pathological bone loss is caused by an imbalance between bone formation and resorption. The bone microenvironments are hypoxic, and hypoxia-inducible factor (HIF) is known to play notable roles in bone remodeling. However, the relevant functions of HIF-2α are not well understood. Here, we have shown that HIF-2α deficiency in mice enhances bone mass through its effects on the differentiation of osteoblasts and osteoclasts. In vitro analyses revealed that HIF-2α inhibits osteoblast differentiation by targeting Twist2 and stimulates RANKL-induced osteoclastogenesis via regulation of Traf6. In addition, HIF-2α appears to contribute to the crosstalk between osteoblasts and osteoclasts by directly targeting RANKL in osteoprogenitor cells. Experiments performed with osteoblast- and osteoclast-specific conditional knockout mice supported a role of HIF-2α in this crosstalk. HIF-2α deficiency alleviated ovariectomy-induced bone loss in mice, and specific inhibition of HIF-2α with ZINC04179524 significantly blocked RANKL-mediated osteoclastogenesis. Collectively, our results suggest that HIF-2α functions as a catabolic regulator in bone remodeling, which is critical for the maintenance of bone homeostasis.

病理性骨丢失是由骨形成和吸收之间的不平衡引起的。骨微环境是缺氧的，并且已知缺氧诱导因子（HIF）在骨骼重塑中起显著作用。但是，HIF-2α的相关功能尚不十分清楚。在这里，我们已经表明，小鼠中的HIF-2α缺乏症通过其对成骨细胞和破骨细胞分化的影响而增强了骨量。体外分析显示，HIF-2α通过靶向Twist2抑制成骨细胞分化，并通过调节Traf6刺激RANKL诱导的破骨细胞生成。另外，HIF-2α似乎通过直接靶向骨祖细胞中的RANKL来促进成骨细胞和破骨细胞之间的串扰。用成骨细胞和破骨细胞特异性条件敲除小鼠进行的实验支持了HIF-2α在这种串扰中的作用。HIF-2α缺乏症减轻了小鼠卵巢切除术引起的骨质流失，并且用ZINC04179524特异性抑制HIF-2α可以显着阻断RANKL介导的破骨细胞生成。总体而言，我们的结果表明，HIF-2α在骨骼重塑中起分解代谢调节剂的作用，这对于维持骨骼的体内稳态至关重要。