[FGF23 and Klotho: the new cornerstones of phosphate/calcium metabolism]

Abstract

Since its first description as a phosphaturic agent in the early 2000’s, the Fibroblast Growth Factor 23 (FGF23) has rapidly become the third key player of phosphate/calcium metabolism with the two ‘old’ PTH and vitamin D. FGF23 is a protein synthesized by osteocytes that acts mainly as a phosphaturic factor and a suppressor of 1α hydroxylase activity in the kidney. It inhibits the expression of type IIa and IIc sodium-phosphate cotransporters on the apical membrane of proximal tubular cells, thus leading to an inhibition of phosphate reabsorption. Moreover, it also inhibits the 1α hydroxylase activity. These two renal pathways account together for the hypophosphatemic effect of FGF23, but FGF23 has also been recently described as an inhibiting factor for PTH synthesis. Its exact role in bone remains to be defined.

A transmembrane protein, Klotho, is an essential cofactor for FGF23 biological activity, but it can also act by itself for calcium and PTH regulation.

This paper gives an overview of these recent data of phosphate/calcium physiology, as well as a description of clinical conditions associated with FGF23 deregulation (genetic diseases and chronic kidney disease). As a conclusion, future therapeutic consequences of the FGF23/Klotho axis are discussed.

Figure 1. les différentes actions du FGF23 en physiologie

PTH: parathormone, hormone hypercalcémiante et phosphaturiante FGF23: Fibroblast Growth Factor 23, hormone phosphaturiante Npt: cotransporteurs sodium-phosphate type II (a et c) DMP1: dental matrix protein 1 PHEX: phosphate-regulating gene with homologies to endopeptidases on X chromosome (+): stimulation (−): inhibition

Figure 2. propriétés biochimiques du FGF23 et implications pratiques

Le clivage du FGF23 au niveau de l’acide aminé 180 (séquence RXXR) permet d’obtenir la forme inactive du FGF23. Les deux dosages du FGF23 sont basés sur des techniques ELISA, en noir un anticorps est dirigé contre la partie N-terminale, et l’autre partie est dirigée contre la partie C-terminale, ce qui permet de ne doser que le FGF23 actif (ou intact). En revanche, lorsque les deux anticorps sont dirigés contre la partie C-terminale (en gris), le FGF23 actif et les fragments C-terminaux sont dosés.