Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation.
Proc Natl Acad Sci U S A
; 111(23): 8673-8, 2014 Jun 10.
Article
en En
| MEDLINE
| ID: mdl-24912186
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Osteogénesis
/
Regulación hacia Arriba
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Subunidad alfa del Factor 1 Inducible por Hipoxia
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Glucólisis
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2014
Tipo del documento:
Article