title: FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner.
abstract: Fibroblast growth factor-23 (Fgf23) is a bone-derived hormone, suppressing phosphate reabsorption and vitamin D hormone (1,25(OH)2 D3 ) production in the kidney. It has long been an enigma why lack of Fgf23 or of Klotho, the coreceptor for Fgf23, leads to severe impairment in bone mineralization despite the presence of hypercalcemia and hyperphosphatemia. Using Fgf23(-/-) or Klotho(-/-) mice together with compound mutant mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor, we show that in Klotho(-/-) mice the mineralization defect is solely driven by 1,25(OH)2 D3 -induced upregulation of the mineralization-inhibiting molecules osteopontin and pyrophosphate in bone. In Fgf23(-/-) mice, the mineralization defect has two components, a 1,25(OH)2 D3 -driven component similar to Klotho(-/-) mice and a component driven by lack of Fgf23, causing additional accumulation of osteopontin. We found that FGF23 regulates osteopontin secretion indirectly by suppressing alkaline phosphatase transcription and phosphate production in osteoblastic cells, acting through FGF receptor-3 in a Klotho-independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization.
authors.affiliation: Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Murali
authors.affiliation: Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.affiliation: Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Ute
authors.initials: U
authors.lastname: Zeitz
authors.affiliation: Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.affiliation: Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Olena
authors.initials: O
authors.lastname: Andrukhova
authors.affiliation: Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D002113:Calcification, Physiologic / Q000502:physiology*; D002117:Calcitriol / Q000235:genetics / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism
chemical_list: C000717428:Fgf23 protein, mouse; D018167:Receptors, Calcitriol; C506896:Spp1 protein, mouse; D053495:Osteopontin; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002117:Calcitriol
keywords: BONE MINERALIZATION; FIBROBLAST GROWTH FACTOR-23 (FGF23); KLOTHO; VITAMIN D