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

doi:10.1038/s41413-019-0054-y

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

Bone Res. 2019 May 13:7:14. doi: 10.1038/s41413-019-0054-y. eCollection 2019.

Authors

Sun Young Lee^#^{1

2}, Ka Hyon Park^#^{1

2}, Hyung-Gu Yu^#², Eunbyul Kook², Won-Hyun Song², Gyuseok Lee², Jeong-Tae Koh^{1

2}, Hong-In Shin³, Je-Yong Choi⁴, Yun Hyun Huh⁵, Je-Hwang Ryu^{1

2}

Affiliations

¹ 1Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186 Korea.
² 2Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, 61186 Korea.
³ 3Department of Oral Pathology and IHBR, School of Dentistry, Kyungpook National University, Daegu, 41940 Korea.
⁴ 4Department of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, Skeletal Diseases Analysis Center, Korea Mouse Phenotyping Center (KMPC), School of Medicine, Kyungpook National University, Daegu, 41944 Korea.
⁵ 5School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005 Korea.

^# Contributed equally.

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.

Keywords: Bone; Diseases.