Controlling hypoxia-inducible factor-2α is critical for maintaining bone homeostasis in mice

• Published in: Bone research 2019-05, Vol.7 (1), p.14-14
• Main Authors: Lee, Sun Young, Park, Ka Hyon, Yu, Hyung-Gu, Kook, Eunbyul, Song, Won-Hyun, Lee, Gyuseok, Koh, Jeong-Tae, Shin, Hong-In, Choi, Je-Yong, Huh, Yun Hyun, Ryu, Je-Hwang
• Format: Article
• Language: English
• Subjects: Homeostasis; Hypoxia
• ISSN: 2095-4700; 2095-6231
• DOI: 10.1038/s41413-019-0054-y

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 and stimulates RANKL-induced osteoclastogenesis via regulation of . 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.