2 research outputs found
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-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