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.Howeve...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 RANKLmediated 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.展开更多
基金supported by the National Research Foundation of Korea(NRF)grant by the Korea government(MSIT)(2012R1A5A2A39671455,NRF-2015R1D1A1A01057870,and NRF-2018R1A2B2006033)the Korea Healthcare Technology R&D Project of the Korea Health Industry Development Institute(HI16C0287 and H114C3484)
文摘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 RANKLmediated 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.
