Journal
BONE
Volume 116, Issue -, Pages 307-314Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2018.08.022
Keywords
Osteocyte; von Hippel-Landau; Hypoxia-inducible factor; Wnt; Sclerostin; Hematopoiesis
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Funding
- University of California Merced faculty research awards
- Veterans Administration [BX001478]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [R01AR053237, R03AR057547, R01AR064255]
- U.S. Department of Energy by Lawrence Livermore National Laboratory [DE-AC52-07NA27344]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR053237, R03AR057547, R01AR064255] Funding Source: NIH RePORTER
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Tissue oxygen (O-2) levels vary during development and disease; adaptations to decreased O-2 (hypoxia) are mediated by hypoxia-inducible factor (HIF) transcription factors. HIFs are active in the skeleton, and stabilizing HIF-alpha isoforms cause high bone mass (HBM) phenotypes. A fundamental limitation of previous studies examining the obligate role for HIF-alpha isoforms in the skeleton involves the persistence of gene deletion as osteolineage cells differentiate into osteocytes. Because osteocytes orchestrate skeletal development and homeostasis, we evaluated the influence of Vhl or Hif1a disruption in osteocytes. Osteocytic Vhl deletion caused HBM phenotype, but Hif1a was dispensable in osteocytes. Vhl cKO mice revealed enhanced canonical Wnt signaling. B cell development was reduced while myelopoiesis increased in osteocytic Vhl cKO, revealing a novel influence of Vhl/HIF-alpha function in osteocytes on maintenance of bone microarchitecture via canonical Wnt signaling and effects on hematopoiesis.
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