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

Colleen Wu, Erinn B. Rankin, Laura Castellini, Javier Fernandez-Alcudia, Edward L. Lagory, Rebecca Andersen, Steven D. Rhodes, Tremika L.S. Wilson, Khalid S. Mohammad, Alesha B. Castillo, Theresa A. Guise, Ernestina Schipani, Amato J. Giaccia

Research output: Contribution to journalArticle

32 Scopus citations

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. Wealso 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.

Original languageEnglish (US)
Pages (from-to)817-831
Number of pages15
JournalGenes and Development
Volume29
Issue number8
DOIs
StatePublished - 2015

Keywords

  • Bone homeostasis
  • HIF signaling
  • Hypoxia
  • Osteoprotegerin
  • Oxygen sensing
  • Prolyl ydroxylase

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Wu, C., Rankin, E. B., Castellini, L., Fernandez-Alcudia, J., Lagory, E. L., Andersen, R., Rhodes, S. D., Wilson, T. L. S., Mohammad, K. S., Castillo, A. B., Guise, T. A., Schipani, E., & Giaccia, A. J. (2015). Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin. Genes and Development, 29(8), 817-831. https://doi.org/10.1101/gad.255000.114