Up-regulation of glycolytic metabolism is required for HIF1?-driven bone formation.

ABSTRACT: 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 (HIF?) proteins, we have investigated the effect of expressing a stabilized form of HIF1? in osteoblast precursors. Brief stabilization of HIF1? 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 HIF1? stabilization. Thus, HIF1?-driven bone formation is independent of VEGFA up-regulation and increased angiogenesis. On the other hand, HIF1? stabilization stimulated glycolysis in bone through up-regulation of key glycolytic enzymes including pyruvate dehydrogenase kinase 1 (PDK1). Pharmacological inhibition of PDK1 completely reversed HIF1?-driven bone formation in vivo. Thus, HIF1? stimulates osteoblast formation through direct activation of glycolysis, and alterations in cellular metabolism may be a broadly applicable mechanism for regulating cell differentiation.

SUBMITTER: Regan JN 

PROVIDER: S-EPMC4060724 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature