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

Sun Young Lee, Ka Hyon Park, Hyung Gu Yu, Eunbyul Kook, Won Hyun Song, Gyuseok Lee, Jeong Tae Koh, Hong In Shin, Je Yong Choi, Yun Hyun Huh, Je Hwang Ryu

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish
Article number14
JournalBone Research
Volume7
Issue number1
DOIs
StatePublished - 1 Dec 2019

Fingerprint

Dive into the research topics of 'Controlling hypoxia-inducible factor-2α is critical for maintaining bone homeostasis in mice'. Together they form a unique fingerprint.

Cite this