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

作者：Jenna N. Regan, Joohyun Lim, Yu Shi, Kyu Sang Joeng, Jeffrey M. Arbeit, Ralph V. Shohet, Fanxin Long · 发表于：Proceedings of the National Academy of Sciences · 年份：2014 · DOI：10.1073/pnas.1324290111 · 被引用次数：189 · 研究领域：Cancer, Hypoxia, and Metabolism、High Altitude and Hypoxia、Metabolism, Diabetes, and Cancer

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 (HIFα) proteins, we have investigated the effect of expressing a stabilized form of HIF1α in osteoblast precursors. Brief stabilization of HIF1α 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 HIF1α stabilization. Thus, HIF1α-driven bone formation is independent of VEGFA up-regulation and increased angiogenesis. On the other hand, HIF1α stabilization stimulated glycolysis in bone through up-regulation of key glycolytic enzymes including pyruvate dehydrogenase kinase 1 (PDK1). Pharmacological inhibition of PDK1 completely reversed HIF1α-driven bone formation in vivo. Thus, HIF1α stimulates osteoblast formation through direct activation of glycolysis, and alterations in cellular metabolism may be a broadly applicable mechanism for regulating cell differentiation.