{"doi":"10.1016/j.bone.2024.117339","title":"Osteocytic oxygen sensing: Distinct impacts of VHL and HIF-2alpha on bone integrity","abstract":"Skeletal fracture resistance emerges from multiple components of bone structure like microarchitecture, matrix mineralization, and organization. These characteristics are engendered via mechanisms like the hypoxia-inducible factors (HIF) pathway, involving two paralogs, HIF-1α and HIF-2α. Under normoxia, HIF-α is targeted for degradation via von-Hippel Lindau (VHL); hypoxia enables HIF-α stabilization and induction of target genes. We previously showed that osteocytic Vhl deletion or expression of degradation-resistant HIF-2α cDR female mice each produced high bone mass, whereas degradation-resistant osteocytic HIF-1α produced no overt phenotype. We report within that Vhl cKO increased bone strength, while HIF-2α cDR displayed markedly reduced bone strength below Cre-negative controls. This suggests that VHL and HIF-2α drive distinct responses that promote disparate effects on bone strength. Both Vhl deletion or HIF-2α accumulation generated two discrete bone morphologies: an outer lamellar cortex and a woven, poorly mineralized endocortex that imparted dramatically different functional outcomes. Our studies reveal novel influence of osteocytic HIF-2α signaling on collagen matrix organization, mineralization, and bone strength. • Vhl deletion and HIF-2α stabilization produce high bone mass with different mechanical properties. • Vhl cKO increases bone strength, while HIF-2α cDR reduces it, despite high bone mass in both. • Both models show poorly mineralized bone, but Vhl cKO has lower remodeling rates. • HIF-2α cDR uniquely alters collagen organization and metabolism. • Vhl and HIF-2α effects highlight HIF-independent pathways in bone health.","journal":"Bone","year":2024,"id":447941,"datarank":0.3268592529447307,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.03497273058643369,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.03497273058643369,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":5,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":218250,"name":"Kristina V Wells","orcid":"0000-0002-4792-912X","position":1,"is_corresponding":false},{"id":335322,"name":"Deepa K. Murugesh","orcid":"0000-0002-4232-8480","position":2,"is_corresponding":false},{"id":237113,"name":"Nicholas R. Hum","orcid":"0000-0003-1605-3193","position":3,"is_corresponding":false},{"id":74820,"name":"Aimy Sebastian","orcid":"0000-0002-7822-7040","position":4,"is_corresponding":false},{"id":1266068,"name":"Bria M. Gorman","orcid":"0000-0002-3360-0956","position":5,"is_corresponding":false},{"id":834673,"name":"Alice Wong","orcid":null,"position":6,"is_corresponding":false},{"id":528349,"name":"Benjamin Osipov","orcid":"0000-0001-9456-3311","position":7,"is_corresponding":false},{"id":293998,"name":"Bernd Christiansen","orcid":"0000-0002-0105-6458","position":8,"is_corresponding":false},{"id":237119,"name":"Gabriela G. Loots","orcid":"0000-0001-9546-5561","position":9,"is_corresponding":false},{"id":226478,"name":"Alexander G. Robling","orcid":"0000-0002-3989-4780","position":10,"is_corresponding":false},{"id":930832,"name":"Clare E. Yellowley","orcid":"0000-0002-1642-513X","position":11,"is_corresponding":false},{"id":294000,"name":"Damian C. Genetos","orcid":"0000-0002-8599-2867","position":12,"is_corresponding":false},{"id":1051767,"name":"Sarah V. Mendoza","orcid":"0000-0002-0947-2755","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:02:03.354708Z","pmid":"39603372","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":[]}