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

Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8673-8. doi: 10.1073/pnas.1324290111. Epub 2014 May 27.

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 (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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Marrow / metabolism
  • Bone Marrow Cells / metabolism
  • Bone and Bones / cytology
  • Bone and Bones / metabolism
  • Cell Hypoxia
  • Female
  • Glycolysis / genetics
  • Glycolysis / physiology*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Osteogenesis / genetics
  • Osteogenesis / physiology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Sp7 Transcription Factor
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Pdk1 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Green Fluorescent Proteins
  • Protein Serine-Threonine Kinases