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Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in

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dc.contributor.author Rauner, Martina
dc.contributor.author Franke, Kristin
dc.contributor.author Murray, Marta
dc.contributor.author Singh, Rashim-Pal
dc.contributor.author Hiram-Bab, Sahar
dc.contributor.author Platzbecker, Uwe
dc.contributor.author Gassmann, Max
dc.contributor.author Socolovsky, Merav
dc.contributor.author Neumann, Drorit
dc.contributor.author Gabet, Yankel
dc.contributor.author Chavakis, Triantafyllos
dc.contributor.author Hofbauer, Lorenz-C.
dc.contributor.author Wielockx, Ben
dc.date.accessioned 2019-02-06T14:45:58Z
dc.date.available 2019-02-06T14:45:58Z
dc.date.issued 2016
dc.identifier.uri https://hdl.handle.net/20.500.12866/5150
dc.description.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. en_US
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof urn:issn:1523-4681
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject BONE LOSS en_US
dc.subject OSTEOBLAST en_US
dc.subject OSTEOCLAST en_US
dc.subject PHD2 en_US
dc.subject Animals en_US
dc.subject Bone Density/genetics en_US
dc.subject Bone Marrow/metabolism/pathology en_US
dc.subject Bone Resorption/genetics/metabolism/pathology en_US
dc.subject Erythropoietin/biosynthesis/genetics en_US
dc.subject Hematopoietic Stem Cells/metabolism/pathology en_US
dc.subject Hypoxia-Inducible Factor-Proline Dioxygenases/deficiency en_US
dc.subject Mice en_US
dc.subject Mice, Knockout en_US
dc.subject Osteoblasts/metabolism/pathology en_US
dc.subject Osteoclasts/metabolism/pathology en_US
dc.title Increased EPO Levels Are Associated With Bone Loss in Mice Lacking PHD2 in en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1002/jbmr.2857
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.00 es_PE
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.18
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.03.11

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