Departments of Orthopaedic Surgery.
Medicine.
Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8673-8. doi: 10.1073/pnas.1324290111. Epub 2014 May 27.
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.
骨髓环境是体内缺氧最严重的环境之一，但缺氧如何影响骨形成尚不清楚。由于低氧张力稳定缺氧诱导因子α（HIFα）蛋白，我们研究了在成骨前体细胞中表达稳定形式的 HIF1α 的效果。在出生后小鼠的 SP7 阳性细胞中短暂稳定 HIF1α，通过显著扩大成骨细胞群体，极大地刺激了松质骨形成。值得注意的是，在小鼠中同时删除血管内皮生长因子 A（VEGFA）并没有减少 HIF1α稳定引起的骨积累。因此，HIF1α 驱动的骨形成不依赖于 VEGFA 的上调和血管生成的增加。另一方面，HIF1α 稳定通过上调关键糖酵解酶，包括丙酮酸脱氢酶激酶 1（PDK1），刺激骨中的糖酵解。PDK1 的药理学抑制完全逆转了体内 HIF1α 驱动的骨形成。因此，HIF1α 通过直接激活糖酵解刺激成骨细胞形成，细胞代谢的改变可能是调节细胞分化的一种广泛适用的机制。
