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Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin

The bone microenvironment is composed of niches that house cells across variable oxygen tensions. However, the contribution of oxygen gradients in regulating bone and blood homeostasis remains unknown. Here, we generated mice with either single or combined genetic inactivation of the critical oxygen...

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Autores principales: Wu, Colleen, Rankin, Erinn B., Castellini, Laura, Fernandez-Alcudia, Javier, LaGory, Edward L., Andersen, Rebecca, Rhodes, Steven D., Wilson, Tremika L.S., Mohammad, Khalid S., Castillo, Alesha B., Guise, Theresa A., Schipani, Ernestina, Giaccia, Amato J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403258/
https://www.ncbi.nlm.nih.gov/pubmed/25846796
http://dx.doi.org/10.1101/gad.255000.114
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author Wu, Colleen
Rankin, Erinn B.
Castellini, Laura
Fernandez-Alcudia, Javier
LaGory, Edward L.
Andersen, Rebecca
Rhodes, Steven D.
Wilson, Tremika L.S.
Mohammad, Khalid S.
Castillo, Alesha B.
Guise, Theresa A.
Schipani, Ernestina
Giaccia, Amato J.
author_facet Wu, Colleen
Rankin, Erinn B.
Castellini, Laura
Fernandez-Alcudia, Javier
LaGory, Edward L.
Andersen, Rebecca
Rhodes, Steven D.
Wilson, Tremika L.S.
Mohammad, Khalid S.
Castillo, Alesha B.
Guise, Theresa A.
Schipani, Ernestina
Giaccia, Amato J.
author_sort Wu, Colleen
collection PubMed
description The bone microenvironment is composed of niches that house cells across variable oxygen tensions. However, the contribution of oxygen gradients in regulating bone and blood homeostasis remains unknown. Here, we generated mice with either single or combined genetic inactivation of the critical oxygen-sensing prolyl hydroxylase (PHD) enzymes (PHD1–3) in osteoprogenitors. Hypoxia-inducible factor (HIF) activation associated with Phd2 and Phd3 inactivation drove bone accumulation by modulating osteoblastic/osteoclastic cross-talk through the direct regulation of osteoprotegerin (OPG). In contrast, combined inactivation of Phd1, Phd2, and Phd3 resulted in extreme HIF signaling, leading to polycythemia and excessive bone accumulation by overstimulating angiogenic–osteogenic coupling. We also demonstrate that genetic ablation of Phd2 and Phd3 was sufficient to protect ovariectomized mice against bone loss without disrupting hematopoietic homeostasis. Importantly, we identify OPG as a HIF target gene capable of directing osteoblast-mediated osteoclastogenesis to regulate bone homeostasis. Here, we show that coordinated activation of specific PHD isoforms fine-tunes the osteoblastic response to hypoxia, thereby directing two important aspects of bone physiology: cross-talk between osteoblasts and osteoclasts and angiogenic–osteogenic coupling.
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spelling pubmed-44032582015-10-15 Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin Wu, Colleen Rankin, Erinn B. Castellini, Laura Fernandez-Alcudia, Javier LaGory, Edward L. Andersen, Rebecca Rhodes, Steven D. Wilson, Tremika L.S. Mohammad, Khalid S. Castillo, Alesha B. Guise, Theresa A. Schipani, Ernestina Giaccia, Amato J. Genes Dev Research Paper The bone microenvironment is composed of niches that house cells across variable oxygen tensions. However, the contribution of oxygen gradients in regulating bone and blood homeostasis remains unknown. Here, we generated mice with either single or combined genetic inactivation of the critical oxygen-sensing prolyl hydroxylase (PHD) enzymes (PHD1–3) in osteoprogenitors. Hypoxia-inducible factor (HIF) activation associated with Phd2 and Phd3 inactivation drove bone accumulation by modulating osteoblastic/osteoclastic cross-talk through the direct regulation of osteoprotegerin (OPG). In contrast, combined inactivation of Phd1, Phd2, and Phd3 resulted in extreme HIF signaling, leading to polycythemia and excessive bone accumulation by overstimulating angiogenic–osteogenic coupling. We also demonstrate that genetic ablation of Phd2 and Phd3 was sufficient to protect ovariectomized mice against bone loss without disrupting hematopoietic homeostasis. Importantly, we identify OPG as a HIF target gene capable of directing osteoblast-mediated osteoclastogenesis to regulate bone homeostasis. Here, we show that coordinated activation of specific PHD isoforms fine-tunes the osteoblastic response to hypoxia, thereby directing two important aspects of bone physiology: cross-talk between osteoblasts and osteoclasts and angiogenic–osteogenic coupling. Cold Spring Harbor Laboratory Press 2015-04-15 /pmc/articles/PMC4403258/ /pubmed/25846796 http://dx.doi.org/10.1101/gad.255000.114 Text en © 2015 Wu et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Wu, Colleen
Rankin, Erinn B.
Castellini, Laura
Fernandez-Alcudia, Javier
LaGory, Edward L.
Andersen, Rebecca
Rhodes, Steven D.
Wilson, Tremika L.S.
Mohammad, Khalid S.
Castillo, Alesha B.
Guise, Theresa A.
Schipani, Ernestina
Giaccia, Amato J.
Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin
title Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin
title_full Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin
title_fullStr Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin
title_full_unstemmed Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin
title_short Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin
title_sort oxygen-sensing phds regulate bone homeostasis through the modulation of osteoprotegerin
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403258/
https://www.ncbi.nlm.nih.gov/pubmed/25846796
http://dx.doi.org/10.1101/gad.255000.114
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