4 research outputs found
The HIF Signaling Pathway in Osteoblasts Directly Modulates Erythropoiesis through the Production of EPO
SummaryOsteoblasts are an important component of the hematopoietic microenvironment in bone. However, the mechanisms by which osteoblasts control hematopoiesis remain unknown. We show that augmented HIF signaling in osteoprogenitors results in HSC niche expansion associated with selective expansion of the erythroid lineage. Increased red blood cell production occurred in an EPO-dependent manner with increased EPO expression in bone and suppressed EPO expression in the kidney. In contrast, inactivation of HIF in osteoprogenitors reduced EPO expression in bone. Importantly, augmented HIF activity in osteoprogenitors protected mice from stress-induced anemia. Pharmacologic or genetic inhibition of prolyl hydroxylases1/2/3 in osteoprogenitors elevated EPO expression in bone and increased hematocrit. These data reveal an unexpected role for osteoblasts in the production of EPO and modulation of erythropoiesis. Furthermore, these studies demonstrate a molecular role for osteoblastic PHD/VHL/HIF signaling that can be targeted to elevate both HSCs and erythroid progenitors in the local hematopoietic microenvironment.PaperCli
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