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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.

Original publication

DOI

10.1016/j.cell.2012.01.051

Type

Journal article

Journal

Cell

Publication Date

30/03/2012

Volume

149

Pages

63 - 74

Keywords

Anemia, Animals, Erythroid Precursor Cells, Erythropoiesis, Erythropoietin, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Mice, Osteoblasts, Signal Transduction, Sp7 Transcription Factor, Transcription Factors, Von Hippel-Lindau Tumor Suppressor Protein