Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

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 alpha) proteins, we have investigated the effect of expressing a stabilized form of HIF1 alpha in osteoblast precursors. Brief stabilization of HIF1 alpha 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 alpha stabilization. Thus, HIF1 alpha-driven bone formation is independent of VEGFA up-regulation and increased angiogenesis. On the other hand, HIF1 alpha 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 alpha-driven bone formation in vivo. Thus, HIF1 alpha stimulates osteoblast formation through direct activation of glycolysis, and alterations in cellular metabolism may be a broadly applicable mechanism for regulating cell differentiation.