title: The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO.
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.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, CA 94303-5152, USA.
authors.forename: Erinn B
authors.initials: EB
authors.lastname: Rankin
authors.forename: Colleen
authors.initials: C
authors.lastname: Wu
authors.forename: Richa
authors.initials: R
authors.lastname: Khatri
authors.forename: Tremika L S
authors.initials: TL
authors.lastname: Wilson
authors.forename: Rebecca
authors.initials: R
authors.lastname: Andersen
authors.forename: Elisa
authors.initials: E
authors.lastname: Araldi
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Rankin
authors.forename: Jenny
authors.initials: J
authors.lastname: Yuan
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Ernestina
authors.initials: E
authors.lastname: Schipani
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D000740:Anemia / Q000517:prevention & control; D000818:Animals; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: C485502:HIF-2 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse