Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 7708503 Tokushima, Japan.
Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 7708503 Tokushima, Japan.
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11418-11427. doi: 10.1073/pnas.1815166116. Epub 2019 May 16.
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 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 , but not , with expected increases in serum FGF23 and Pi in mice. 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 in osteoblasts/osteocytes abrogated high Pi diet-induced increases in serum FGF23 and femoral 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.
成纤维细胞生长因子 23（FGF23）由骨骼产生，是一种降低血清磷酸盐（Pi）的激素。反映其在 Pi 控制中的核心作用，血清 FGF23 受到血清 Pi 变化的严格调节。FGF23 的水平受到转录事件和翻译后切割为无活性片段的调节，然后再分泌。对于后者，基因产物通过 O-糖基化使 FGF23 免受切割，导致血清 FGF23 增加。然而，在调节血清 FGF23 方面，Pi 感应的分子基础仍然难以捉摸。在这项研究中，我们表明高 Pi 饮食增强了骨骼中 的表达，但不是 ，预期血清 FGF23 和 Pi 增加。在成骨细胞 UMR 106 细胞中进一步观察到高 Pi 诱导的 诱导，这是通过细胞外信号调节激酶（ERK）途径的激活介导的。通过对高 Pi 的上游传感器进行蛋白质组学搜索，我们鉴定出一种 FGFR 亚型（FGFR1c），在没有 FGFs 的情况下，高 Pi 可使其磷酸化。高 Pi 激活无配体 FGFR 的模式与 FGFR 与典型 FGFR 配体（FGF2）结合时不同，当监测 FGFR 底物 2α 和 ERK 的磷酸化时。最后，我们表明，FGFR 抑制剂和成骨细胞/成骨细胞中 的条件性缺失消除了高 Pi 饮食诱导的血清 FGF23 和股骨 表达增加在小鼠中。因此，这些发现揭示了未被识别的无配体 FGFR 功能的一个方面，并说明了参与 FGF23 产生调节的 Pi 感应途径。
