{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T15:08:49Z","timestamp":1789398529397,"version":"build-2803163510"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"U.S. Department of Energy by Lawrence Livermore National Laboratory","award":["DE-421AC52-07NA27344"],"award-info":[{"award-number":["DE-421AC52-07NA27344"]}]},{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health","award":["R01 AR0737722"],"award-info":[{"award-number":["R01 AR0737722"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Osteocytes regulate skeletal homeostasis and respond to oxygen deprivation via hypoxia-inducible factors (HIFs), the principal transcriptional mediators of the cellular hypoxia response. There are 2 transcriptionally active HIF-\u03b1 paralogs, HIF-1\u03b1 and HIF-2\u03b1, that have overlapping and distinct transcriptional targets. Under normoxic conditions, the E3 ubiquitin ligase Von Hippel\u2013Lindau (VHL) acts as the master regulator of HIFs by targeting them for proteasomal degradation, whereas hypoxia prevents this, allowing for HIF stabilization and accumulation. Osteocyte-enriched deletion of Vhl (Vhl cKO) produces a high bone mass (HBM) phenotype. Vhl loss stabilizes both HIFs, leaving their distinct contributions to this HBM phenotype undefined. To dissect their role in osteocytes, we developed compound Vhl; Hif1a cKO, Vhl; Hif2a cKO mice, mice expressing individual and combined degradation-resistant (cDR) paralogs HIF-1\u03b1 (HIF-\u03b1 cDR), HIF-2\u03b1 (HIF-2\u03b1 cDR), and HIF-1\u03b1; HIF-2\u03b1 cDR and evaluated their impact on bone structure and function. Micro-CT revealed that Vhl cKO mice exhibited the highest trabecular bone volume fraction, a phenotype not fully reproduced in any HIF-modified genotype. Among partial phenocopies, Vhl; Hif2a cKO produced the largest partial increase, followed by Vhl; Hif1a cKO, and HIF-2\u03b1 cDR. HIF-1\u03b1; HIF-2\u03b1 cDR displayed modest elevation, while cre-negative and HIF-1\u03b1 cDR were indistinguishable. Cortical area expansion required Vhl deletion and was not reproduced by single-paralog HIF stabilization. While Vhl cKO femora exhibited significantly increased whole-bone mechanical properties relative to sex- and age-matched controls, all HIF-modified genotypes had similar material properties and HIF-2\u03b1 activation appeared to compromise material integrity. HIF-1\u03b1 and HIF-2\u03b1 therefore exert non-redundant, compartment-specific roles in the Vhl cKO HBM phenotype and are each required for maximal bone integrity. Yet, no HIF-modified genotype, including dual HIF-1\u03b1\/HIF-2\u03b1 stabilization, reproduced the Vhl cKO phenotype, implicating the possibility of VHL functions beyond HIF stabilization in the full skeletal response.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziag148","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:57:24Z","timestamp":1788289044000},"source":"Crossref","is-referenced-by-count":0,"title":["Dissecting Hypoxia Inducible Factor-Driven High Bone Mass Phenotype in Mice Lacking Osteocytic Von Hippel-Lindau"],"prefix":"10.1093","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6501-6634","authenticated-orcid":false,"given":"Adriana P","family":"Pantoja","sequence":"first","affiliation":[{"name":"Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis , Davis, CA 95616 ,","place":["United 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, Sacramento, CA 95817 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9546-5561","authenticated-orcid":false,"given":"Gabriela G","family":"Loots","sequence":"additional","affiliation":[{"name":"Lawrence Livermore National Laboratories , Livermore, CA 94550 ,","place":["United States"]},{"name":"Department of Orthopaedic Surgery, University of California Davis Health , Sacramento, CA 95817 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8599-2867","authenticated-orcid":false,"given":"Damian C","family":"Genetos","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis , Davis, CA 95616 ,","place":["United 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