%0 Journal Article
%T Controlling hypoxia-inducible factor-2¦Á is critical for maintaining bone homeostasis in mice
%J -
%D 2019
%R https://doi.org/10.1038/s41413-019-0054-y
%X 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-2¦Á are not well understood. Here, we have shown that HIF-2¦Á deficiency in mice enhances bone mass through its effects on the differentiation of osteoblasts and osteoclasts. In vitro analyses revealed that HIF-2¦Á inhibits osteoblast differentiation by targeting Twist2 and stimulates RANKL-induced osteoclastogenesis via regulation of Traf6. In addition, HIF-2¦Á 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-2¦Á in this crosstalk. HIF-2¦Á deficiency alleviated ovariectomy-induced bone loss in mice, and specific inhibition of HIF-2¦Á with ZINC04179524 significantly blocked RANKL-mediated osteoclastogenesis. Collectively, our results suggest that HIF-2¦Á functions as a catabolic regulator in bone remodeling, which is critical for the maintenance of bone homeostasis
%U https://www.nature.com/articles/s41413-019-0054-y