title: Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation.
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.
authors.affiliation: Departments of Orthopaedic Surgery.
authors.forename: Jenna N
authors.initials: JN
authors.lastname: Regan
authors.affiliation: Departments of Orthopaedic Surgery.
authors.forename: Joohyun
authors.initials: J
authors.lastname: Lim
authors.affiliation: Departments of Orthopaedic Surgery.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Medicine.
authors.forename: Kyu Sang
authors.initials: KS
authors.lastname: Joeng
authors.affiliation: Surgery, and.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Arbeit
authors.affiliation: Department of Medicine, University of Hawaii, Honolulu, HI 96813.
authors.forename: Ralph V
authors.initials: RV
authors.lastname: Shohet
authors.affiliation: Departments of Orthopaedic Surgery,Medicine,Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110; and longf@wudosis.wustl.edu.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D015687:Cell Hypoxia; D005260:Female; D006019:Glycolysis / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases