| First Author | Guo W | Year | 2023 |
| Journal | Sci Transl Med | Volume | 15 |
| Issue | 724 | Pages | eabo5217 |
| PubMed ID | 38019933 | Mgi Jnum | J:352513 |
| Mgi Id | MGI:7567538 | Doi | 10.1126/scitranslmed.abo5217 |
| Citation | Guo W, et al. (2023) Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2alpha in skeletal progenitor cells. Sci Transl Med 15(724):eabo5217 |
| abstractText | Radiotherapy remains a common treatment modality for cancer despite skeletal complications. However, there are currently no effective treatments for radiation-induced bone loss, and the consequences of radiotherapy on skeletal progenitor cell (SPC) survival and function remain unclear. After radiation, leptin receptor-expressing cells, which include a population of SPCs, become localized to hypoxic regions of the bone and stabilize the transcription factor hypoxia-inducible factor-2alpha (HIF-2alpha), thus suggesting a role for HIF-2alpha in the skeletal response to radiation. Here, we conditionally knocked out HIF-2alpha in leptin receptor-expressing cells and their descendants in mice. Radiation therapy in littermate control mice reduced bone mass; however, HIF-2alpha conditional knockout mice maintained bone mass comparable to nonirradiated control animals. HIF-2alpha negatively regulated the number of SPCs, bone formation, and bone mineralization. To test whether blocking HIF-2alpha pharmacologically could reduce bone loss during radiation, we administered a selective HIF-2alpha inhibitor called PT2399 (a structural analog of which was recently FDA-approved) to wild-type mice before radiation exposure. Pharmacological inhibition of HIF-2alpha was sufficient to prevent radiation-induced bone loss in a single-limb irradiation mouse model. Given that ~90% of patients who receive a HIF-2alpha inhibitor develop anemia because of off-target effects, we developed a bone-targeting nanocarrier formulation to deliver the HIF-2alpha inhibitor to mouse bone, to increase on-target efficacy and reduce off-target toxicities. Nanocarrier-loaded PT2399 prevented radiation-induced bone loss in mice while reducing drug accumulation in the kidney. Targeted inhibition of HIF-2alpha may represent a therapeutic approach for protecting bone during radiation therapy. |
