# Targeting the HIF-2 Signaling Pathway as a Radioprotective Strategy for Bone

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $354,200

## Abstract

PROJECT SUMMARY
While radiation therapy effectively eliminates malignant cells, damage to healthy tissue surrounding tumors
remains a persistent clinical issue. Indeed, cancer patients who receive radiation treatment have an increased
risk for fracture when compared to those who undergo the same treatment regimen but who are not subjected
to radiotherapy. Unfortunately, the use of antiresorptive agents such as bisphosphates does not significantly
reduce insufficiency fractures for this patient population. For these reasons, our long-term goal is to identify
unique cellular and molecular mechanisms that can be therapeutically exploited for the radioprotection of bone.
Notably, the bone microenvironment (BME) is characterized by low oxygen tension or hypoxia. In response to
this external stimulus, many cell types in the BME activate hypoxia inducible factor (HIF) signaling to facilitate
cell survival. While activation of the HIF signaling pathway is required to maintain healthy bone, the contribution
of hypoxia/HIF signaling during radiation induced bone damage has not been well defined. Intriguingly, we show
irradiated bones show a decrease in multipotent mesenchymal progenitors (MMPs) when compared to non-
irradiated controls. Moreover, preliminary data shows that MMPs are found in hypoxic regions and respond to
hypoxia by stabilizing HIF-2. Strikingly, while conditional ablation of HIF-2 in a population of MMPs did not alter
bone homeostasis, it did serve to protect against bone loss after radiation exposure. For these reasons, our
overarching hypothesis is that genetic and pharmacological inhibition of HIF-2 will serve as a radioprotective
mechanism to ameliorate bone damage after radiation exposure, in part, by maintaining the number of MMPs
that can functionally contribute to bone after stress induced damage. To test our hypothesis, we will utilize a
combination of genetically engineered mouse models, in vitro cell culture experiments, and novel
pharmacological approaches to inhibit the HIF-2 signaling pathway in the BME. Currently, there are no FDA
approved agents to mitigate radiation induced bone loss, hence these studies will not only expand our
fundamental knowledge of bone biology but will also fill an unmet clinical need to identify therapeutic targets
which will ameliorate bone damage after radiotherapy.

## Key facts

- **NIH application ID:** 10500053
- **Project number:** 1R01AR081303-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Colleen Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $354,200
- **Award type:** 1
- **Project period:** 2022-07-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500053

## Citation

> US National Institutes of Health, RePORTER application 10500053, Targeting the HIF-2 Signaling Pathway as a Radioprotective Strategy for Bone (1R01AR081303-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10500053. Licensed CC0.

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