title: Fibroblast growth factor-23 abolishes 1,25-dihydroxyvitamin D₃-enhanced duodenal calcium transport in male mice.
abstract: Despite being widely recognized as the important bone-derived phosphaturic hormone, whether fibroblast growth factor (FGF)-23 modulated intestinal calcium absorption remained elusive. Since FGF-23 could reduce the circulating level of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], FGF-23 probably compromised the 1,25(OH)₂D₃-induced intestinal calcium absorption. FGF-23 may also exert an inhibitory action directly through FGF receptors (FGFR) in the intestinal cells. Herein, we demonstrated by Ussing chamber technique that male mice administered 1 μg/kg 1,25(OH)₂D₃ sc daily for 3 days exhibited increased duodenal calcium absorption, which was abolished by concurrent intravenous injection of recombinant mouse FGF-23. This FGF-23 administration had no effect on the background epithelial electrical properties, i.e., short-circuit current, transepithelial potential difference, and resistance. Immunohistochemical evidence of protein expressions of FGFR isoforms 1-4 in mouse duodenal epithelial cells suggested a possible direct effect of FGF-23 on the intestine. This was supported by the findings that FGF-23 directly added to the serosal compartment of the Ussing chamber and completely abolished the 1,25(OH)₂D₃-induced calcium absorption in the duodenal tissues taken from the 1,25(OH)₂D₃-treated mice. However, direct FGF-23 exposure did not decrease the duodenal calcium absorption without 1,25(OH)₂D₃ preinjection. The observed FGF-23 action was mediated by MAPK/ERK, p38 MAPK, and PKC. Quantitative real-time PCR further showed that FGF-23 diminished the 1,25(OH)₂D₃-induced upregulation of TRPV5, TRPV6, and calbindin-D(9k), but not PMCA(1b) expression in the duodenal epithelial cells. In conclusion, besides being a phosphatonin, FGF-23 was shown to be a novel calcium-regulating hormone that acted directly on the mouse intestine, thereby compromising the 1,25(OH)₂D₃-induced calcium absorption.
authors.affiliation: Center of Calcium and Bone Research, Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Pissared
authors.initials: P
authors.lastname: Khuituan
authors.forename: Jarinthorn
authors.initials: J
authors.lastname: Teerapornpuntakit
authors.forename: Kannikar
authors.initials: K
authors.lastname: Wongdee
authors.forename: Panan
authors.initials: P
authors.lastname: Suntornsaratoon
authors.forename: Nipaporn
authors.initials: N
authors.lastname: Konthapakdee
authors.forename: Jintana
authors.initials: J
authors.lastname: Sangsaksri
authors.forename: Chanakarn
authors.initials: C
authors.lastname: Sripong
authors.forename: Nateetip
authors.initials: N
authors.lastname: Krishnamra
authors.forename: Narattaphol
authors.initials: N
authors.lastname: Charoenphandhu
mesh_terms: D000818:Animals; D064026:Calbindins; D002117:Calcitriol / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002136:Calcium, Dietary / Q000378:metabolism*; D016764:Cell Polarity; D004386:Duodenum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D064026:Calbindins; D015220:Calcium Channels; D002136:Calcium, Dietary; C000717428:Fgf23 protein, mouse; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D064030:S100 Calcium Binding Protein G; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C446923:Trpv6 protein, mouse; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002117:Calcitriol