Background

Inorganic 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 findings

Our recent results indicate that the post-translational modification of FGF23 protein through a gene product of GALNT3 is 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 of GALNT3.

Conclusions

We 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.

中文翻译：

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FGF23 产生的磷酸盐感应和调节机制。

 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导致佝偻病/骨软化症和异位钙化，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 Pi 水平的主要激素。 FGF23 由骨骼产生，尤其是由成骨细胞和骨细胞产生，通过与肾脏中的 FGF 受体 (FGFR) 1c 和 α-Klotho 复合物结合发挥作用。 FGF23 通过降低血清 1,25-二羟基维生素 D 水平来抑制肾脏磷酸盐重吸收和肠道磷酸盐吸收，从而降低血清 Pi 水平。目前尚不清楚骨骼如何感知血清Pi水平的变化以及骨骼如何调节FGF23的产生。

 最近的发现

我们最近的研究结果表明，通过GALNT3基因产物对 FGF23 蛋白进行翻译后修饰是高膳食 Pi 增强 FGF23 产生的主要调节机制。此外，高细胞外Pi直接激活FGFR1及其下游细胞内信号通路调节GALNT3的表达水平。

 结论

我们认为 FGFR1 作为 Pi 传感受体调节 FGF23 的产生和血清 Pi 水平。血清Pi的调节涉及FGFR1和FGF23，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开发新的治疗方法来治疗由 Pi 水平异常引起的疾病。