Phosphate-sensing and regulatory mechanism of FGF23 production
Phosphate-sensing and regulatory mechanism of FGF23 production
复制标题
FGF23 产生的磷酸盐传感和调控机制
DOI：
10.1007/s40618-020-01205-9
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发表时间：
2020
影响因子：
5.4
通讯作者：
Fukumoto S.
中科院分区：
文献类型：
--
作者：
Takashi Y.;Fukumoto S.
背景无机磷酸盐（Pi）是人体必需的矿物质。低磷血症和高磷血症分别引起佝偻病/骨软化和异位钙化，表明需要调节血清Pi水平。成纤维细胞生长因子（FGF）23是调节血清磷水平的主要激素。FGF 23由骨产生，特别是由成骨细胞和骨细胞产生，并通过与肾脏中的FGF受体（FGFR）1c和α-Klotho复合物结合而起作用。FGF 23通过降低血清1，25-二羟维生素D水平抑制肾磷酸盐重吸收和肠磷酸盐吸收来降低血清Pi水平。目前尚不清楚骨骼是如何感受血清磷水平的变化以及骨骼是如何调节FGF 23的产生的。我们最近的研究结果表明，通过GALNT 3基因产物对FGF 23蛋白的翻译后修饰是高磷促进FGF 23产生的主要调节机制。此外，高细胞外Pi直接激活FGFR 1，其下游细胞内信号通路调节GALNT 3的表达水平。结论FGFR 1作为Pi敏感受体参与FGF 23的产生和血清Pi水平的调节。在FGFR 1和FGF 23参与的血清Pi调节中存在负反馈系统，这是内分泌调节的基本机制。这些发现可能会导致新的治疗方法的发展，以治疗由异常Pi水平引起的疾病。
BackgroundInorganic phosphate (Pi) is an essential mineral for human. Hypophosphatemia and hyperphosphatemia cause rickets/osteomalacia and ectopic calcification, respectively, indicating that serum Pi level needs to be regulated. Fibroblast growth factor (FGF) 23 is a principal hormone to regulate serum Pi level. FGF23 is produced by the bone, especially by the osteoblasts and osteocytes, and works by binding to FGF receptor (FGFR) 1c and α-Klotho complex in the kidney. FGF23 reduces serum Pi level by inhibiting both renal phosphate reabsorption and intestinal phosphate absorption via reduction of serum 1,25-dihydroxyvitamin D level. It has been unclear how the bone senses changes of serum Pi level and how the bone regulates the production of FGF23.Recent findingsOur recent results indicate that the post-translational modification of FGF23 protein through a gene product ofGALNT3is the main regulatory mechanism of enhanced FGF23 production by high dietary Pi. Furthermore, high extracellular Pi directly activates FGFR1 and its downstream intracellular signaling pathway regulates the expression level ofGALNT3.ConclusionsWe propose that FGFR1 works as a Pi-sensing receptor in the regulation of FGF23 production and serum Pi level. There is a negative feedback system, which is a basic mechanism of endocrine regulation, in the regulation of serum Pi involving FGFR1, and FGF23. These findings may lead to the development of new therapeutic methods to treat diseases caused by abnormal Pi level.