| First Author | Regan JN | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 23 | Pages | 8673-8 |
| PubMed ID | 24912186 | Mgi Jnum | J:211709 |
| Mgi Id | MGI:5576075 | Doi | 10.1073/pnas.1324290111 |
| Citation | Regan JN, et al. (2014) Up-regulation of glycolytic metabolism is required for HIF1alpha-driven bone formation. Proc Natl Acad Sci U S A 111(23):8673-8 |
| abstractText | The bone marrow environment is among the most hypoxic in the body, but how hypoxia affects bone formation is not known. Because low oxygen tension stabilizes hypoxia-inducible factor alpha (HIFalpha) proteins, we have investigated the effect of expressing a stabilized form of HIF1alpha in osteoblast precursors. Brief stabilization of HIF1alpha in SP7-positive cells in postnatal mice dramatically stimulated cancellous bone formation via marked expansion of the osteoblast population. Remarkably, concomitant deletion of vascular endothelial growth factor A (VEGFA) in the mouse did not diminish bone accrual caused by HIF1alpha stabilization. Thus, HIF1alpha-driven bone formation is independent of VEGFA up-regulation and increased angiogenesis. On the other hand, HIF1alpha stabilization stimulated glycolysis in bone through up-regulation of key glycolytic enzymes including pyruvate dehydrogenase kinase 1 (PDK1). Pharmacological inhibition of PDK1 completely reversed HIF1alpha-driven bone formation in vivo. Thus, HIF1alpha stimulates osteoblast formation through direct activation of glycolysis, and alterations in cellular metabolism may be a broadly applicable mechanism for regulating cell differentiation. |
