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Osteoblasts control erythropoiesis via the HIF signaling pathway


It has been known for some time that osteoblasts play a major role in regulating erythropoiesis, but the mechanism involved has not been elucidated. In this study, the researchers generated mice with osteoprogenitor cells that exhibited either HIF-1 and HIF-2 overexpression or inactivation. These two HIF-α homologs control skeletal homeostasis by influencing HIF signaling in osteoblasts, and by regulating erythropoietin (EPO) expression in mature mice.

Mice overexpressing HIF-1 and HIF-2 showed excessive accumulation of trabecular bone in their long bones, with trabecular bone volume increased 2.5 fold; this was associated with elevated levels of trabecular osteoblasts and hypervascularisation, and selective expansion of erythropoietic cells of all lineages. An increase in red blood cell production, directly correlated with increased EPO expression in bone, was observed. HIF-1 and HIF-2 inactivation had the opposite effect.

Editor's comment: This study demonstrated for the first time that osteoblasts produce EPO through an HIF-dependent mechanism, and that local EPO production by osteoblasts can drive erythropoiesis. Furthermore, enhancement of HIF signaling by prolyl hydroxylase inhibitors can enhance both erythropoiesis and hematopoietic stem cell (HSC) expansion. Thus, manipulation of HIF signaling in osteoblasts can provide a new therapeutic strategy for HSC niche expansion with selective increase in erythroid lineage.

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