title: The metabolic bone disease associated with theHypmutation is independent of osteoblastic HIF1α expression.
abstract: Fibroblast growth factor-23 (FGF23) controls key responses to systemic phosphate increases through its phosphaturic actions on the kidney. In addition to stimulation by phosphate, FGF23 positively responds to iron deficiency anemia and hypoxia in rodent models and in humans. The disorder X-linked hypophosphatemia (XLH) is characterized by elevated FGF23 in concert with an intrinsic bone mineralization defect. Indeed, theHypmouse XLH model has disturbed osteoblast to osteocyte differentiation with altered expression of a wide variety of genes, including FGF23. The transcription factor Hypoxia inducible factor-1α (HIF1α) has been implicated in regulating FGF23 production and plays a key role in proper bone cell differentiation. Thus the goals of this study were to determine whether HIF1α activation could influence FGF23, and to test osteoblastic HIF1α production on theHypendocrine and skeletal phenotypesin vivo. Treatment of primary cultures of osteoblasts/osteocytes and UMR-106 cells with the HIF activator AG490 resulted in rapid HIF1α stabilization and increased Fgf23 mRNA (50-100 fold;p< 0.01-0.001) in a time- and dose-dependent manner. Next, thePhexgene deletion in theHypmouse was bred onto mice with a HIF1α/Osteocalcin (OCN)-Cre background. Although HIF1α effects on bone could be detected, FGF23-related phenotypes due to theHypmutation were independent of HIF1αin vivo. In summary, FGF23 can be driven by ectopic HIF1α activation under normal iron conditionsin vitro, but factors independent of HIF1α activity after mature osteoblast formation are responsible for the disease phenotypes inHypmicein vivo.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Hum
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Clinkenbeard
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Colin
authors.initials: C
authors.lastname: Ip
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Taryn A
authors.initials: TA
authors.lastname: Cass
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Matt
authors.initials: M
authors.lastname: Allen
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: White
keywords: FGF23; Hypoxia inducible factor-1α; Phosphate; X-linked hypophosphatemia