Differential but complementary roles of HIF-1α and HIF-2α in the regulation of bone homeostasis
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 o...
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Veröffentlicht in: | Communications biology 2024-07, Vol.7 (1), p.892-12, Article 892 |
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Sprache: | eng |
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Zusammenfassung: | 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.
HIF-1α plays an important role in bone homeostasis by upregulating Twist2 to suppress RUNX2 and regulate osteoblast differentiation, while also influencing osteoclast formation by regulating RANKL secretion through HIF-2a. |
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ISSN: | 2399-3642 2399-3642 |
DOI: | 10.1038/s42003-024-06581-z |