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

Colleen Wu, Erinn B. Rankin1, Laura Castellini, Javier Fernandez-Alcudia, Edward L. Lagory, Rebecca Andersen, Steven D. Rhodes, Tremika L S Wilson, Khalid Mohammad, Alesha B. Castillo, Theresa Guise, Ernestina Schipani, Amato J. Giaccia

Research output: Contribution to journalArticle

28 Citations (Scopus)

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

Fingerprint

Osteoprotegerin
Homeostasis
Oxygen
Bone and Bones
Prolyl Hydroxylases
Osteoblasts
Polycythemia
Osteoclasts
Osteogenesis
Protein Isoforms
Hypoxia
Enzymes
Genes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Wu, C., Rankin1, E. B., Castellini, L., Fernandez-Alcudia, J., Lagory, E. L., Andersen, R., ... 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

Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin. / Wu, Colleen; Rankin1, Erinn B.; Castellini, Laura; Fernandez-Alcudia, Javier; Lagory, Edward L.; Andersen, Rebecca; Rhodes, Steven D.; Wilson, Tremika L S; Mohammad, Khalid; Castillo, Alesha B.; Guise, Theresa; Schipani, Ernestina; Giaccia, Amato J.

In: Genes and Development, Vol. 29, No. 8, 2015, p. 817-831.

Research output: Contribution to journalArticle

Wu, C, Rankin1, EB, Castellini, L, Fernandez-Alcudia, J, Lagory, EL, Andersen, R, Rhodes, SD, Wilson, TLS, Mohammad, K, Castillo, AB, Guise, T, Schipani, E & Giaccia, AJ 2015, 'Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin', Genes and Development, vol. 29, no. 8, pp. 817-831. https://doi.org/10.1101/gad.255000.114
Wu C, Rankin1 EB, Castellini L, Fernandez-Alcudia J, Lagory EL, Andersen R et al. Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin. Genes and Development. 2015;29(8):817-831. https://doi.org/10.1101/gad.255000.114
Wu, Colleen ; Rankin1, Erinn B. ; Castellini, Laura ; Fernandez-Alcudia, Javier ; Lagory, Edward L. ; Andersen, Rebecca ; Rhodes, Steven D. ; Wilson, Tremika L S ; Mohammad, Khalid ; Castillo, Alesha B. ; Guise, Theresa ; Schipani, Ernestina ; Giaccia, Amato J. / Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin. In: Genes and Development. 2015 ; Vol. 29, No. 8. pp. 817-831.
@article{4d152dfa7d3c493dbbf742e1f0329de9,
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. 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.",
keywords = "Bone homeostasis, HIF signaling, Hypoxia, Osteoprotegerin, Oxygen sensing, Prolyl ydroxylase",
author = "Colleen Wu and Rankin1, {Erinn B.} and Laura Castellini and Javier Fernandez-Alcudia and Lagory, {Edward L.} and Rebecca Andersen and Rhodes, {Steven D.} and Wilson, {Tremika L S} and Khalid Mohammad and Castillo, {Alesha B.} and Theresa Guise and Ernestina Schipani and Giaccia, {Amato J.}",
year = "2015",
doi = "10.1101/gad.255000.114",
language = "English (US)",
volume = "29",
pages = "817--831",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "8",

}

TY - JOUR

T1 - Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin

AU - Wu, Colleen

AU - Rankin1, Erinn B.

AU - Castellini, Laura

AU - Fernandez-Alcudia, Javier

AU - Lagory, Edward L.

AU - Andersen, Rebecca

AU - Rhodes, Steven D.

AU - Wilson, Tremika L S

AU - Mohammad, Khalid

AU - Castillo, Alesha B.

AU - Guise, Theresa

AU - Schipani, Ernestina

AU - Giaccia, Amato J.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Bone homeostasis

KW - HIF signaling

KW - Hypoxia

KW - Osteoprotegerin

KW - Oxygen sensing

KW - Prolyl ydroxylase

UR - http://www.scopus.com/inward/record.url?scp=84927776927&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927776927&partnerID=8YFLogxK

U2 - 10.1101/gad.255000.114

DO - 10.1101/gad.255000.114

M3 - Article

C2 - 25846796

AN - SCOPUS:84927776927

VL - 29

SP - 817

EP - 831

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 8

ER -