Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin
- Colleen Wu1,
- Erinn B. Rankin1,2,
- Laura Castellini1,
- Javier Fernandez-Alcudia3,
- Edward L. LaGory1,
- Rebecca Andersen1,8,9,
- Steven D. Rhodes4,5,
- Tremika L.S. Wilson6,10,11,
- Khalid S. Mohammad4,6,
- Alesha B. Castillo7,12,
- Theresa A. Guise6,
- Ernestina Schipani6,10,11 and
- Amato J. Giaccia1
- 1Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA;
- 2Department of Obstetrics and Gynecology, Stanford University, Stanford, California 94305, USA;
- 3Department of Dermatology, Stanford University, Stanford, California 94305, USA;
- 4Department of Anatomy and Cell Biology, Indiana School of Medicine, Indianapolis, Indiana 46202, USA;
- 5Department of Medicine, Indiana School of Medicine, Indianapolis, Indiana 46202, USA;
- 6Division of Endocrinology, Department of Medicine, Indiana School of Medicine, Indianapolis, Indiana 46202, USA;
- 7Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University, Stanford, California 94305, USA
- Corresponding author: giaccia{at}stanford.edu
Abstract
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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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.255000.114.
- Received October 28, 2014.
- Accepted March 11, 2015.
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