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
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Blotting, Western
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Bone Marrow / metabolism
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Bone Marrow Cells / metabolism
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Bone and Bones / cytology
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Bone and Bones / metabolism
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Cell Hypoxia
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Female
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Glycolysis / genetics
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Glycolysis / physiology*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Hypoxia
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Immunohistochemistry
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Male
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Mice
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Mice, Knockout
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Mice, Transgenic
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Microscopy, Confocal
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Osteoblasts / cytology
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Osteoblasts / metabolism
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Osteogenesis / genetics
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Osteogenesis / physiology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Sp7 Transcription Factor
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Up-Regulation*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Pdk1 protein, mouse
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Sp7 Transcription Factor
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Sp7 protein, mouse
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Transcription Factors
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Green Fluorescent Proteins
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Protein Serine-Threonine Kinases