{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lee SY"],"funding":["National Research Foundation of Korea (NRF)","National Research Foundation of Korea"],"pagination":["892"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11263705"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7(1)"],"pubmed_abstract":["Bone is a highly dynamic tissue undergoing continuous formation and resorption. Here, we investigated differential but complementary roles of hypoxia-inducible factor (HIF)-1α and HIF-2α in regulating bone remodeling. Using RNA-seq analysis, we identified that specific genes involved in regulating osteoblast differentiation were similarly but slightly differently governed by HIF-1α and HIF-2α. We found that increased HIF-1α expression inhibited osteoblast differentiation via inhibiting RUNX2 function by upregulation of Twist2, confirmed using Hif1a conditional knockout (KO) mouse. Ectopic expression of HIF-1α via adenovirus transduction resulted in the increased expression and activity of RANKL, while knockdown of Hif1a expression via siRNA or osteoblast-specific depletion of Hif1a in conditional KO mice had no discernible effect on osteoblast-mediated osteoclast activation. The unexpected outcome was elucidated by the upregulation of HIF-2α upon Hif1a overexpression, providing evidence that Hif2a is a transcriptional target of HIF-1α in regulating RANKL expression, verified through an experiment of HIF-2α knockdown after HIF-1α overexpression. The above results were validated in an ovariectomized- and aging-induced osteoporosis model using Hif1a conditional KO mice. Our findings conclude that HIF-1α plays an important role in regulating bone homeostasis by controlling osteoblast differentiation, and in influencing osteoclast formation through the regulation of RANKL secretion via HIF-2α modulation."],"journal":["Communications biology"],"pubmed_title":["Differential but complementary roles of HIF-1α and HIF-2α in the regulation of bone homeostasis."],"pmcid":["PMC11263705"],"funding_grant_id":["2021R1A2C3005727","2019R1A5A2027521"],"pubmed_authors":["Park KH","Lee SY","Oh Y","Huh YH","Ryu JH","Kim SJ","Lee G"],"additional_accession":[]},"is_claimable":false,"name":"Differential but complementary roles of HIF-1α and HIF-2α in the regulation of bone homeostasis.","description":"Bone is a highly dynamic tissue undergoing continuous formation and resorption. Here, we investigated differential but complementary roles of hypoxia-inducible factor (HIF)-1α and HIF-2α in regulating bone remodeling. Using RNA-seq analysis, we identified that specific genes involved in regulating osteoblast differentiation were similarly but slightly differently governed by HIF-1α and HIF-2α. We found that increased HIF-1α expression inhibited osteoblast differentiation via inhibiting RUNX2 function by upregulation of Twist2, confirmed using Hif1a conditional knockout (KO) mouse. Ectopic expression of HIF-1α via adenovirus transduction resulted in the increased expression and activity of RANKL, while knockdown of Hif1a expression via siRNA or osteoblast-specific depletion of Hif1a in conditional KO mice had no discernible effect on osteoblast-mediated osteoclast activation. The unexpected outcome was elucidated by the upregulation of HIF-2α upon Hif1a overexpression, providing evidence that Hif2a is a transcriptional target of HIF-1α in regulating RANKL expression, verified through an experiment of HIF-2α knockdown after HIF-1α overexpression. The above results were validated in an ovariectomized- and aging-induced osteoporosis model using Hif1a conditional KO mice. Our findings conclude that HIF-1α plays an important role in regulating bone homeostasis by controlling osteoblast differentiation, and in influencing osteoclast formation through the regulation of RANKL secretion via HIF-2α modulation.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2026-06-23T03:12:06.056Z","creation":"2026-06-23T03:09:35.289Z"},"accession":"S-EPMC11263705","cross_references":{"pubmed":["39039245"],"doi":["10.1038/s42003-024-06581-z"]}}