title: The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia.
abstract: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-1α (HIF-1α) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-1α mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-1α and FGF23 were co-localized in spindle-shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-1α protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-1α expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-1α inhibitors decreased HIF-1α and FGF23 protein accumulation and inhibited HIF-1α-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-1α consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-1α inhibitor. These results show for the first time that HIF-1α is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-1α activity in TIO contributes to the aberrant FGF23 production in these patients.
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Doucet
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Tomlinson
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center , Memphis, TN, USA.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center , Memphis, TN, USA.
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
authors.affiliation: Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institutes of Health , Bethesda, MD, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Collins
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, MD, USA; Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Clemens