ID 113621
Author
Takashi, Yuichi Tokushima University|The University of Tokyo Tokushima University Educator and Researcher Directory
Kinoshita, Yuka The University of Tokyo
Ito, Nobuaki The University of Tokyo
Tsoumpra, Maria K. Tokushima University
Nangaku, Masaomi The University of Tokyo
Kato, Shigeaki Iryo Sosei University|Tokiwa Foundation
Content Type
Journal Article
Description
Fibroblast growth factor (FGF) 23 produced by bone is a hormone that decreases serum phosphate (Pi). Reflecting its central role in Pi control, serum FGF23 is tightly regulated by serum Pi alterations. FGF23 levels are regulated by the transcriptional event and posttranslational cleavage into inactive fragments before its secretion. For the latter, O-glycosylation of FGF23 by GALNT3 gene product prevents the cleavage, leading to an increase in serum FGF23. However, the molecular basis of Pi sensing in the regulation of serum FGF23 remains elusive. In this study, we showed that high Pi diet enhanced the skeletal expression of Galnt3, but not Fgf23, with expected increases in serum FGF23 and Pi in mice. Galnt3 induction by high Pi was further observed in osteoblastic UMR 106 cells, and this was mediated by activation of the extracellular signal-regulated kinase (ERK) pathway. Through proteomic searches for the upstream sensor for high Pi, we identified one subtype of the FGF receptor (FGFR1c), which was phosphorylated by high Pi in the absence of FGFs. The mode of unliganded FGFR activation by high Pi appeared different from that of FGFR bound to a canonical FGFR ligand (FGF2) when phosphorylation of the FGFR substrate 2α and ERK was monitored. Finally, we showed that an FGFR inhibitor and conditional deletion of Fgfr1 in osteoblasts/osteocytes abrogated high Pi diet-induced increases in serum FGF23 and femoral Galnt3 expression in mice. Thus, these findings uncover an unrecognized facet of unliganded FGFR function and illustrate a Pi-sensing pathway involved in regulation of FGF23 production.
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
ISSN
00278424
10916490
NCID
AA11726874
Publisher
National Academy of Sciences
Volume
116
Issue
23
Start Page
11418
End Page
11427
Published Date
2019-05-16
Rights
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND)(http://creativecommons.org/licenses/by-nc-nd/4.0/).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Publisher
departments
Institute of Advanced Medical Sciences
Medical Sciences