Hypoxia-inducible factor 2α is a negative regulator of osteoblastogenesis and bone mass accrual

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. Bone formation: Signaling in the opposite direction The regulation of gene expression by hypoxia-inducible factor 2 (HIF2) prevents bone formation by inhibiting the differentiation of mesenchymal cells into osteoblasts. Ernestina Schipani at the University of Michigan, USA, and colleagues found that the bone mass of mice expressing a stabilized version of HIF2 was reduced compared with controls. This effect was associated with HIF2−mediated activation of the transcription factor SOX9, which disrupts osteoblastogenesis and stimulates the formation of cartilage cells. Interestingly, HIF1, which shares 48% overall amino acid identity with HIF2, is an established positive regulator of bone formation. These findings suggest that the opposing actions of HIF1 and HIF2 could be key for regulating bone growth. Furthermore, they raise the interesting possibility of using HIF2 inhibitors for the treatment of diseases characterized by low bone mass such as osteoporosis.