{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T16:40:00Z","timestamp":1785516000484,"version":"3.56.0"},"reference-count":52,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"724","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,11,29]]},"abstract":"<jats:p>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\u2013expressing cells, which include a population of SPCs, become localized to hypoxic regions of the bone and stabilize the transcription factor hypoxia-inducible factor-2\u03b1 (HIF-2\u03b1), thus suggesting a role for HIF-2\u03b1 in the skeletal response to radiation. Here, we conditionally knocked out HIF-2\u03b1 in leptin receptor\u2013expressing cells and their descendants in mice. Radiation therapy in littermate control mice reduced bone mass; however, HIF-2\u03b1 conditional knockout mice maintained bone mass comparable to nonirradiated control animals. HIF-2\u03b1 negatively regulated the number of SPCs, bone formation, and bone mineralization. To test whether blocking HIF-2\u03b1 pharmacologically could reduce bone loss during radiation, we administered a selective HIF-2\u03b1 inhibitor called PT2399 (a structural analog of which was recently FDA-approved) to wild-type mice before radiation exposure. Pharmacological inhibition of HIF-2\u03b1 was sufficient to prevent radiation-induced bone loss in a single-limb irradiation mouse model. Given that ~90% of patients who receive a HIF-2\u03b1 inhibitor develop anemia because of off-target effects, we developed a bone-targeting nanocarrier formulation to deliver the HIF-2\u03b1 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-2\u03b1 may represent a therapeutic approach for protecting bone during radiation therapy.<\/jats:p>","DOI":"10.1126\/scitranslmed.abo5217","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T18:59:02Z","timestamp":1701284342000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":16,"title":["Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2\u03b1 in skeletal progenitor cells"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1199-0818","authenticated-orcid":true,"given":"Wendi","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC 27705, USA."},{"name":"Department of Pharmacology &amp; Cancer Biology, Duke University School of Medicine, Durham, NC 27705, 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