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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2015
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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. |
format | Online Article Text |
id | pubmed-4403258 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
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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