title: Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease.
abstract: Secondary hyperparathyroidism, in which parathyroid hormone (PTH) is excessively secreted in response to factors such as hyperphosphataemia, hypocalcaemia, and low 1,25-dihydroxyvitamin D (1,25(OH)2D) levels, is commonly observed in patients with chronic kidney disease (CKD), and is accompanied by high levels of fibroblast growth factor 23 (FGF23). However, the effect of FGF23 on the parathyroid glands (PG) remains controversial. To bind to FGF receptors, FGF23 requires αKlotho, which is highly expressed in the PG. Here, we examined the effects of Fgfr1-3, αKlotho, or Fgfr1-4 ablation specifically in the PG (conditional knockout, cKO). When mice with early to mid-stage CKD with and without cKO were compared, plasma concentrations of calcium, phosphate, FGF23, and 1,25(OH)2D did not change significantly. In contrast, plasma PTH levels, which were elevated in CKD mice, were significantly decreased in cKO mice. PG from CKD mice showed augmentation of cell proliferation, which was significantly suppressed by cKO. Parathyroid tissue cultured for 4 days showed upregulation of PTH secretion and cell proliferation in response to FGF23. Both these effects were inhibited by cKO. These findings suggest that FGF23 is a long-term inducer of parathyroid cell proliferation and PTH secretion, and is one cause of secondary hyperparathyroidism in CKD.
authors.affiliation: Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Takeshita
authors.affiliation: Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Kenryo
authors.initials: K
authors.lastname: Furushima
authors.affiliation: Laboratory Animal Center, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Miyajima
authors.affiliation: Division of Molecular Medicine, Kansai University of Health Sciences, Kumatori 590-0482, Japan.
authors.forename: Ikuji
authors.initials: I
authors.lastname: Hatamura
authors.affiliation: Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.affiliation: Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, 2-2-3 Minatojima Minami-machi, Chuou-ku, Kobe 650-0047, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Furuta
authors.affiliation: Department of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006962:Hyperparathyroidism, Secondary / Q000209:etiology* / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D010280:Parathyroid Glands / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D015398:Signal Transduction
chemical_list: C000717428:Fgf23 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins