Degradation-Resistant Hypoxia Inducible Factor-2α in Murine Osteocytes Promotes a High Bone Mass Phenotype.

Autor: Mendoza SV; Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine University of California Davis Davis CA USA., Murugesh DK; Lawrence Livermore National Laboratories Physical and Life Sciences Directorate Livermore CA USA., Christiansen BA; Department of Orthopaedic Surgery University of California Davis Health Sacramento CA USA., Genetos ZO; Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine University of California Davis Davis CA USA., Loots GG; Lawrence Livermore National Laboratories Physical and Life Sciences Directorate Livermore CA USA., Genetos DC; Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine University of California Davis Davis CA USA., Yellowley CE; Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine University of California Davis Davis CA USA.
Jazyk: angličtina
Zdroj: JBMR plus [JBMR Plus] 2023 Feb 17; Vol. 7 (4), pp. e10724. Date of Electronic Publication: 2023 Feb 17 (Print Publication: 2023).
DOI: 10.1002/jbm4.10724
Abstrakt: Molecular oxygen levels vary during development and disease. Adaptations to decreased oxygen bioavailability (hypoxia) are mediated by hypoxia-inducible factor (HIF) transcription factors. HIFs are composed of an oxygen-dependent α subunit (HIF-α), of which there are two transcriptionally active isoforms (HIF-1α and HIF-2α), and a constitutively expressed β subunit (HIFβ). Under normoxic conditions, HIF-α is hydroxylated via prolyl hydroxylase domain (PHD) proteins and targeted for degradation via Von Hippel-Lindau (VHL). Under hypoxic conditions, hydroxylation via PHD is inhibited, allowing for HIF-α stabilization and induction of target transcriptional changes. Our previous studies showed that Vhl deletion in osteocytes ( Dmp1-cre; Vhl f/f ) resulted in HIF-α stabilization and generation of a high bone mass (HBM) phenotype. The skeletal impact of HIF-1α accumulation has been well characterized; however, the unique skeletal impacts of HIF-2α remain understudied. Because osteocytes orchestrate skeletal development and homeostasis, we investigated the role of osteocytic HIF-α isoforms in driving HBM phenotypes via osteocyte-specific loss-of-function and gain-of-function HIF-1α and HIF-2α mutations in C57BL/6 female mice. Deletion of Hif1a or Hif2a in osteocytes showed no effect on skeletal microarchitecture. Constitutively stable, degradation-resistant HIF-2α (HIF-2α cDR), but not HIF-1α cDR, generated dramatic increases in bone mass, enhanced osteoclast activity, and expansion of metaphyseal marrow stromal tissue at the expense of hematopoietic tissue. Our studies reveal a novel influence of osteocytic HIF-2α in driving HBM phenotypes that can potentially be harnessed pharmacologically to improve bone mass and reduce fracture risk. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Competing Interests: All authors declare that they have no relevant or material financial interests that relate to the research described in this paper.
(© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)
Databáze: MEDLINE
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