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

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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-2 fl/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 aP2CreRosa26 tdTomato/+ 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, condition

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

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