title: Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin.
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.
authors.affiliation: Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA;
authors.forename: Colleen
authors.initials: C
authors.lastname: Wu
authors.affiliation: Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA; Department of Obstetrics and Gynecology, Stanford University, Stanford, California 94305, USA;
authors.forename: Erinn B
authors.initials: EB
authors.lastname: Rankin
authors.affiliation: Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA;
authors.forename: Laura
authors.initials: L
authors.lastname: Castellini
authors.forename: Javier F
authors.initials: JF
authors.lastname: Alcudia
authors.affiliation: Department of Dermatology, Stanford University, Stanford, California 94305, USA;
authors.forename: Javier
authors.initials: J
authors.lastname: Fernandez-Alcudia
authors.affiliation: Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA;
authors.forename: Edward L
authors.initials: EL
authors.lastname: LaGory
authors.affiliation: Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Andersen
authors.affiliation: Department of Anatomy and Cell Biology, Indiana School of Medicine, Indianapolis, Indiana 46202, USA; Department of Medicine, Indiana School of Medicine, Indianapolis, Indiana 46202, USA;
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rhodes
authors.affiliation: Division of Endocrinology, Department of Medicine, Indiana School of Medicine, Indianapolis, Indiana 46202, USA;
authors.forename: Tremika L S
authors.initials: TL
authors.lastname: Wilson
authors.affiliation: Department of Anatomy and Cell Biology, Indiana School of Medicine, Indianapolis, Indiana 46202, USA; Division of Endocrinology, Department of Medicine, Indiana School of Medicine, Indianapolis, Indiana 46202, USA;
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University, Stanford, California 94305, USA.
authors.forename: Alesha B
authors.initials: AB
authors.lastname: Castillo
authors.affiliation: Division of Endocrinology, Department of Medicine, Indiana School of Medicine, Indianapolis, Indiana 46202, USA;
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.affiliation: Division of Endocrinology, Department of Medicine, Indiana School of Medicine, Indianapolis, Indiana 46202, USA;
authors.forename: Ernestina
authors.initials: E
authors.lastname: Schipani
authors.affiliation: Division of Cancer and Radiation Oncology, Department of Radiation Oncology, Stanford University, Stanford, California 94305, USA; giaccia@stanford.edu.
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001862:Bone Resorption / Q000235:genetics; D001842:Bone and Bones / Q000166:cytology / Q000201:enzymology*; D002450:Cell Communication; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D020868:Gene Silencing; D006706:Homeostasis; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D064828:Prolyl Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000201:enzymology
chemical_list: D051793:Hypoxia-Inducible Factor 1; D053244:Osteoprotegerin; D064828:Prolyl Hydroxylases; D010100:Oxygen
keywords: HIF signaling; bone homeostasis; hypoxia; osteoprotegerin; oxygen sensing; prolyl hydroxylase
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