In Vivo Loss of Hypoxia-Inducible Factor-2a in Osteoblastic Cells Leads to a High Trabecular Bone Mass Phenotype

Osteoblast lineage cells within adult bone marrow are exposed to varying oxygen levels. Hypoxia-Inducible Factor-1a (HIF1a) and HIF2a are pivotal in the cellular response to hypoxia. Our study explores the effects of targeted HIF2a deletion in mesenchymal progenitors and their descendants. We demonstrate that HIF2a acts as a negative regulator of osteoblastogenesis and bone mass accrual. Therapeutically targeting HIF2a could be beneficial in treating low bone mass conditions, such as those observed in chronic diseases, osteoporosis, or during aging. To elucidate the mechanisms underlying the increased bone mass resulting from HIF2a loss, we performed single-cell RNA sequencing (scRNA-seq) on bone marrow stromal cells from both mutant mice lacking HIF2a in PRX1 lineage cells and control mice.