Abstract
Osteoblasts, which are the bone-forming cells, operate in a hypoxic environment. The transcription factors hypoxia-inducible factor-1α (HIF1) and HIF2 are key mediators of the cellular response to hypoxia. Both are expressed in osteoblasts. HIF1 is known to be a positive regulator of bone formation. Conversely, the role of HIF2 in the control osteoblast biology is still poorly understood. In this study, we used mouse genetics to demonstrate that HIF2 is an inhibitor of osteoblastogenesis and bone mass accrual. Moreover, we provided evidence that HIF2 impairs osteoblast differentiation at least in part, by upregulating the transcription factor Sox9. Our findings constitute a paradigm shift, as activation of the hypoxia-signaling pathway has traditionally been associated with increased bone formation through HIF1. Inhibiting HIF2 could thus represent a therapeutic approach for the treatment of the low bone mass observed in chronic diseases, osteoporosis, or aging.
Highlights
In the developing and adult skeleton, osteoblasts are the boneforming cells and they originate from mesenchymal progenitors present in the periosteum and bone marrow.[1,2] Notably, these mesenchymal progenitors can give origin to chondrocytes in vitro when cultured in appropriate conditions.[3]
Neither impairment of bone resorption nor polycythemia occurred upon expression of a gain-of-function mutation of hypoxia-inducible factor1α (HIF1) in the same cells.[8]. These findings suggest that HIF2 may have a unique and distinct role in osteoblastic cells when compared with HIF1
Heterozygous mutant mice (PRX-HIF2dPAf/+) were viable, and displayed a severe bone phenotype when compared with control mice (HIF2dPAf/+); because the two prolines that are the targets of the PHDs are generation of homozygous mutants was not pursued
Summary
In the developing and adult skeleton, osteoblasts are the boneforming cells and they originate from mesenchymal progenitors present in the periosteum and bone marrow.[1,2] Notably, these mesenchymal progenitors can give origin to chondrocytes in vitro when cultured in appropriate conditions.[3]. The osteoblast–osteoclast coupling allows for bone growth during development, and maintenance of bone and mineral homeostasis in adulthood.[7]
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