| First Author | Lee SY | Year | 2024 |
| Journal | Commun Biol | Volume | 7 |
| Issue | 1 | Pages | 892 |
| PubMed ID | 39039245 | Mgi Jnum | J:352132 |
| Mgi Id | MGI:7704361 | Doi | 10.1038/s42003-024-06581-z |
| Citation | Lee SY, et al. (2024) Differential but complementary roles of HIF-1alpha and HIF-2alpha in the regulation of bone homeostasis. Commun Biol 7(1):892 |
| abstractText | Bone is a highly dynamic tissue undergoing continuous formation and resorption. Here, we investigated differential but complementary roles of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha 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-1alpha and HIF-2alpha. We found that increased HIF-1alpha expression inhibited osteoblast differentiation via inhibiting RUNX2 function by upregulation of Twist2, confirmed using Hif1a conditional knockout (KO) mouse. Ectopic expression of HIF-1alpha 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-2alpha upon Hif1a overexpression, providing evidence that Hif2a is a transcriptional target of HIF-1alpha in regulating RANKL expression, verified through an experiment of HIF-2alpha knockdown after HIF-1alpha overexpression. The above results were validated in an ovariectomized- and aging-induced osteoporosis model using Hif1a conditional KO mice. Our findings conclude that HIF-1alpha 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-2alpha modulation. |
