title: Fgf23 and parathyroid hormone signaling interact in kidney and bone.
abstract: Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, suppressing renal phosphate reabsorption and vitamin D hormone synthesis in proximal tubules, and stimulating calcium reabsorption in distal tubules of the kidney. Here, we analyzed the long term sequelae of deficient Fgf23 signaling on bone and mineral metabolism in 9-month-old mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor (VDR). To prevent hypocalcemia in VDR deficient mice, all mice were kept on a rescue diet enriched with calcium, phosphate, and lactose. VDR mutants were normocalcemic and normophosphatemic, and had normal tibial bone mineral density. Relative to VDR mutants, Fgf23/VDR and Klotho/VDR compound mutants were characterized by hypocalcemia, hyperphosphatemia, and very high serum parathyroid hormone (PTH). Despite ∼10-fold higher serum PTH levels in compound mutants, urinary excretion of phosphate and calcium as well as osteoclast numbers in bone remained unchanged relative to VDR mutants. The increase in plasma cAMP after hPTH(1-34) injection was similar in all genotypes. However, a 5-day infusion of hPTH(1-34) via osmotic minipumps resulted in reduced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in bone and kidney of Fgf23/VDR and Klotho/VDR compound mutants, relative to VDR and WT controls. Similarly, the PTH-mediated ERK1/2 phosphorylation was reduced in primary osteoblasts isolated from Fgf23 and Klotho deficient mice, but was restored by concomitant treatment with recombinant FGF23. Collectively, our data indicate that the phosphaturic, calcium-conserving, and bone resorption-stimulating actions of PTH are blunted by Fgf23 or Klotho deficiency. Hence, FGF23 may be an important modulator of PTH signaling in bone and kidney.
authors: Department of Biomedical Sciences, University of Veterinary Medicine, 1210, Vienna, Austria.
authors: Olena
authors: O
authors: Andrukhova
authors: Department of Biomedical Sciences, University of Veterinary Medicine, 1210, Vienna, Austria.
authors: Carmen
authors: C
authors: Streicher
authors: Department of Biomedical Sciences, University of Veterinary Medicine, 1210, Vienna, Austria.
authors: Ute
authors: U
authors: Zeitz
authors: Department of Biomedical Sciences, University of Veterinary Medicine, 1210, Vienna, Austria. Electronic address: Reinhold.Erben@vetmeduni.ac.at.
authors: Reinhold G
authors: RG
authors: Erben
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000172:deficiency / Q000378:metabolism; D006961:Hyperparathyroidism / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D000090265:Klotho Proteins; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D015220:Calcium Channels; C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Bone; Fibroblast growth factor-23; Parathyroid hormone; Secondary hyperparathyroidism; Vitamin D