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PMID: 22464323 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO.

Cell ·Vol. 149 ·No. 1 ·2012-03-30 ·Pages 63-74

Rankin EB, Wu C, Khatri R, Wilson TL, Andersen R, Araldi E, Rankin AL, Yuan J, Kuo CJ, Schipani E, Giaccia AJ

Abstract

Osteoblasts are an important component of the hematopoietic microenvironment in bone. However, the mechanisms by which osteoblasts control hematopoiesis remain unknown. We show that augmented HIF signaling in osteoprogenitors results in HSC niche expansion associated with selective expansion of the erythroid lineage. Increased red blood cell production occurred in an EPO-dependent manner with increased EPO expression in bone and suppressed EPO expression in the kidney. In contrast, inactivation of HIF in osteoprogenitors reduced EPO expression in bone. Importantly, augmented HIF activity in osteoprogenitors protected mice from stress-induced anemia. Pharmacologic or genetic inhibition of prolyl hydroxylases1/2/3 in osteoprogenitors elevated EPO expression in bone and increased hematocrit. These data reveal an unexpected role for osteoblasts in the production of EPO and modulation of erythropoiesis. Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment.

MeSH Terms
Anemia/prevention & control Animals Erythroid Precursor Cells/metabolism Erythropoiesis Erythropoietin/metabolism Hypoxia-Inducible Factor 1, alpha Subunit/genetics,metabolism Kidney/metabolism Mice Osteoblasts/metabolism Signal Transduction Sp7 Transcription Factor Transcription Factors/genetics,metabolism Von Hippel-Lindau Tumor Suppressor Protein/metabolism
Chemicals
HIF-2 protein, mouse Hif1a protein, mouse Hypoxia-Inducible Factor 1, alpha Subunit Sp7 Transcription Factor Sp7 protein, mouse Transcription Factors Erythropoietin Von Hippel-Lindau Tumor Suppressor Protein VHL protein, mouse
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Rankin Erinn B
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, CA 94303-5152, USA.
Wu Colleen
Khatri Richa
Wilson Tremika L S
Andersen Rebecca
Araldi Elisa
Rankin Andrew L
Yuan Jenny
Kuo Calvin J
Schipani Ernestina
Giaccia Amato J
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.01.051
Published
2012-03-30
Pages
63-74
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3408231
Subset
IM
Grants
NCI NIH HHS · P01 CA067166 · United States
NCI NIH HHS · R01 CA116685 · United States
NCI NIH HHS · CA67166 · United States
NIDDK NIH HHS · U01 DK085527 · United States
NCI NIH HHS · T32 CA09151 · United States
NIAMS NIH HHS · R01 AR048191 · United States
NCI NIH HHS · CA088480 · United States
CIHR · Canada
NCI NIH HHS · T32 CA009151 · United States
NIAMS NIH HHS · AR048191-06 · United States
NCI NIH HHS · R37 CA088480 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2012.01.051 PMC Full Text View journal details
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