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

Area of Science:

• Bone biology and radiation oncology
• Cellular and molecular mechanisms of bone microenvironment (BME) regulation

Background:

• Radiation therapy, while crucial for cancer treatment, causes significant damage to normal tissues, particularly bone.
• Radiation-induced bone toxicity includes hematopoietic dysfunction, reduced bone volume, and increased marrow adipose tissue (MAT), leading to higher fracture risk.
• The bone marrow microenvironment (BME) is typically hypoxic, activating hypoxia-inducible factor (HIF) signaling, which plays a role in cellular responses to stress.

Purpose of the Study:

• To investigate the role of hypoxia/HIF signaling in radiation-induced marrow adipose tissue (MAT) expansion.
• To identify the specific cell populations and signaling pathways involved in regulating MAT following radiation exposure.

Main Methods:

• Generated and analyzed conditional knockout mice (aP2Cre;Hif-1fl/fl;Hif-2fl/fl) to assess HIF signaling in aP2-expressing cells after radiation.
• Utilized lineage tracing with aP2CreRosa26tdTomato/+ mice to track the differentiation of aP2-expressing cells.
• Examined the effect of HIFα transcription factor ablation in LepRCre-expressing skeletal stem cells on radiation-induced MAT expansion.

Main Results:

• Radiation exposure led to rapid and persistent MAT accumulation, with adipocytes localizing to hypoxic regions.
• Conditional deletion of HIF signaling in aP2-expressing cells unexpectedly exacerbated radiation-induced MAT expansion compared to controls.
• Lineage tracing indicated that aP2-expressing cells do not primarily differentiate into adipocytes, macrophages, or endothelial cells, but rather influence MAT formation via an uncharacterized stromal population.
• Ablation of HIFα in LepRCre-expressing skeletal stem cells did not affect radiation-induced MAT expansion.

Conclusions:

• Findings reveal a previously unrecognized population of adipocyte-regulatory cells where HIF-dependent activity normally constrains stress-induced marrow adiposity.
• This study provides novel mechanistic insights into how radiation disrupts the bone marrow microenvironment and promotes MAT expansion.
• The results advance the understanding of cellular and molecular drivers of radiation-induced bone fragility and identify potential therapeutic targets.