Hypoxia/HIF Signaling Negatively Regulates Bone Marrow Adiposity after Radiation Exposure

Radiation therapy is an essential cancer treatment, yet collateral damage to normal tissues remains a major clinical challenge. In bone, radiation-induced toxicity is characterized by loss of hematopoietic function, reduced bone volume, and increased marrow adipose tissue (MAT). Importantly, cancer patients who undergo radiotherapy exhibit significantly higher fracture risk compared to those receiving similar treatments without radiation exposure, underscoring the clinical consequences of bone microenvironment (BME) injury. The BME is inherently hypoxic resulting in the activation of by hypoxia-inducible factor (HIF) signaling. Here, we demonstrate that radiation induces a rapid and persistent accumulation of MAT, with adipocytes localizing preferentially to hypoxic regions of the marrow. To investigate the role of hypoxia/HIF signaling in this process, we generated aP2Cre;Hif-1 fl/fl;Hif-2fl/fl conditional knockout mice. Surprisingly, these mice exhibited increased MAT expansion following radiation compared to controls, suggesting that HIF deletion in aP2-expressing cells exacerbates radiation-induced adipogenesis. Analysis aP2CreRosa26tdTomato/+ mice revealed that most aP2-expressing cells did not give rise to mature adipocytes, macrophages, or endothelial cells, pointing instead to an uncharacterized stromal population that influences MAT formation. In contrast, conditional ablation of HIF transcription factors in LepRCre-expressing skeletal stem cells, which contain a subpopulation of skeletal progenitors which directly contribute to marrow adipocytes, had no effect on radiation-induced MAT expansion. Collectively, these findings identify a previously unrecognized population of adipocyte-regulatory cells whose HIF-dependent activity constrains stress-induced marrow adiposity. This work provides new mechanistic insight into how radiation disrupts the marrow microenvironment and expands MAT, advancing our understanding of the cellular and molecular drivers of radiation-induced bone fragility. One Sentence SummaryLoss of HIF signaling in aP2Cre expressing cells enhances radiation induced marrow adiposity.