title: Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in EPO-Producing Cells.
abstract: The main oxygen sensor hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2) is a critical regulator of tissue homeostasis during erythropoiesis, hematopoietic stem cell maintenance, and wound healing. Recent studies point toward a role for the PHD2-erythropoietin (EPO) axis in the modulation of bone remodeling, even though the studies produced conflicting results. Here, we used a number of mouse strains deficient of PHD2 in different cell types to address the role of PHD2 and its downstream targets HIF-1α and HIF-2α in bone remodeling. Mice deficient for PHD2 in several cell lineages, including EPO-producing cells, osteoblasts, and hematopoietic cells (CD68:cre-PHD2f/f) displayed a severe reduction of bone density at the distal femur as well as the vertebral body due to impaired bone formation but not bone resorption. Importantly, using osteoblast-specific (Osx:cre-PHD2f/f) and osteoclast-specific PHD2 knock-out mice (Vav:cre- PHD2f/f), we show that this effect is independent of the loss of PHD2 in osteoblast and osteoclasts. Using different in vivo and in vitro approaches, we show here that this bone phenotype, including the suppression of bone formation, is directly linked to the stabilization of the α-subunit of HIF-2, and possibly to the subsequent moderate induction of serum EPO, which directly influenced the differentiation and mineralization of osteoblast progenitors resulting in lower bone density. Taken together, our data identify the PHD2:HIF-2α:EPO axis as a so far unknown regulator of osteohematology by controlling bone homeostasis. Further, these data suggest that patients treated with PHD inhibitors or EPO should be monitored with respect to their bone status. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany.|Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Franke
authors.affiliation: Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany.|Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Murray
authors.affiliation: Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany.|Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Rashim Pal
authors.initials: RP
authors.lastname: Singh
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Sahar
authors.initials: S
authors.lastname: Hiram-Bab
authors.affiliation: Department of Medicine I, Technische Universität Dresden, Dresden, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.|Zurich Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland.|Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru.
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA.|Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Merav
authors.initials: M
authors.lastname: Socolovsky
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Drorit
authors.initials: D
authors.lastname: Neumann
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.
authors.forename: Yankel
authors.initials: Y
authors.lastname: Gabet
authors.affiliation: Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany.|Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.|Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Department of Medicine III, Technische Universität Dresden, Dresden, Germany.|Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.affiliation: Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany. Ben.Wielockx@tu-dresden.de.|Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany. Ben.Wielockx@tu-dresden.de.|Center for Regenerative Therapies Dresden, Dresden, Germany. Ben.Wielockx@tu-dresden.de.
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology
chemical_list: D004921:Erythropoietin; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: BONE LOSS; ERYTHROPOIETIN; OSTEOBLAST; OSTEOCLAST; PHD2