{"doi":"10.1126/scitranslmed.abo5217","title":"Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2α in skeletal progenitor cells","abstract":"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-2α (HIF-2α), thus suggesting a role for HIF-2α in the skeletal response to radiation. Here, we conditionally knocked out HIF-2α in leptin receptor-expressing cells and their descendants in mice. Radiation therapy in littermate control mice reduced bone mass; however, HIF-2α conditional knockout mice maintained bone mass comparable to nonirradiated control animals. HIF-2α negatively regulated the number of SPCs, bone formation, and bone mineralization. To test whether blocking HIF-2α pharmacologically could reduce bone loss during radiation, we administered a selective HIF-2α inhibitor called PT2399 (a structural analog of which was recently FDA-approved) to wild-type mice before radiation exposure. Pharmacological inhibition of HIF-2α was sufficient to prevent radiation-induced bone loss in a single-limb irradiation mouse model. Given that ~90% of patients who receive a HIF-2α inhibitor develop anemia because of off-target effects, we developed a bone-targeting nanocarrier formulation to deliver the HIF-2α 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-2α may represent a therapeutic approach for protecting bone during radiation therapy.","journal":"Science Translational Medicine","year":2023,"id":330442,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":662476,"name":"Jiaul Hoque","orcid":null,"position":1,"is_corresponding":false},{"id":428198,"name":"Carolina J. García García","orcid":"0000-0001-8330-1746","position":2,"is_corresponding":false},{"id":782301,"name":"Kassandra V. Spiller","orcid":null,"position":3,"is_corresponding":false},{"id":808065,"name":"Abigail Leinroth","orcid":"0000-0001-5754-8577","position":4,"is_corresponding":false},{"id":252807,"name":"Vijitha Puviindran","orcid":null,"position":5,"is_corresponding":false},{"id":1054172,"name":"Cahil Potnis","orcid":"0000-0002-0749-0343","position":6,"is_corresponding":false},{"id":1054680,"name":"Kiana A. Gunn","orcid":null,"position":7,"is_corresponding":false},{"id":619115,"name":"Hunter Newman","orcid":"0000-0003-0264-9957","position":8,"is_corresponding":false},{"id":1054173,"name":"Koji Ishikawa","orcid":"0000-0003-3689-5662","position":9,"is_corresponding":false},{"id":815088,"name":"Tara N. Fujimoto","orcid":"0000-0002-1685-9173","position":10,"is_corresponding":false},{"id":1054681,"name":"Denae Neill","orcid":null,"position":11,"is_corresponding":false},{"id":815688,"name":"Abagail Delahoussaye","orcid":null,"position":12,"is_corresponding":false},{"id":491684,"name":"Nerissa T. Williams","orcid":"0000-0003-0554-9222","position":13,"is_corresponding":false},{"id":334422,"name":"David G. Kirsch","orcid":"0000-0002-2086-205X","position":14,"is_corresponding":false},{"id":250591,"name":"Matthew J. Hilton","orcid":"0000-0003-3165-267X","position":15,"is_corresponding":false},{"id":619117,"name":"Shyni Varghese","orcid":"0000-0002-0004-7947","position":16,"is_corresponding":false},{"id":60605,"name":"Cullen M. Taniguchi","orcid":"0000-0002-8052-3316","position":17,"is_corresponding":false},{"id":483245,"name":"Colleen Wu","orcid":"0000-0002-8459-8243","position":18,"is_corresponding":false},{"id":407473,"name":"Wendi Guo","orcid":"0000-0002-1199-0818","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T01:09:10.120703Z","pmid":"38019933","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}