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

Jenna Regan, Joohyun Lim, Yu Shi, Kyu Sang Joeng, Jeffrey M. Arbeit, Ralph V. Shohet, Fanxin Longa

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)8673-8678
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number23
DOIs
StatePublished - Jun 10 2014

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Osteogenesis
Up-Regulation
Osteoblasts
Glycolysis
Vascular Endothelial Growth Factor A
Bone and Bones
Cell Differentiation
Bone Marrow
Pharmacology
Oxygen
Enzymes
Population
Proteins
Hypoxia
pyruvate dehydrogenase (acetyl-transferring) kinase

ASJC Scopus subject areas

  • General

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Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation. / Regan, Jenna; Lim, Joohyun; Shi, Yu; Joeng, Kyu Sang; Arbeit, Jeffrey M.; Shohet, Ralph V.; Longa, Fanxin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 23, 10.06.2014, p. 8673-8678.

Research output: Contribution to journalArticle

Regan, Jenna ; Lim, Joohyun ; Shi, Yu ; Joeng, Kyu Sang ; Arbeit, Jeffrey M. ; Shohet, Ralph V. ; Longa, Fanxin. / Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 23. pp. 8673-8678.
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AU - Shohet, Ralph V.

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