The couple fibroblast growth factor 23 (FGF23)/Klotho

The fibrobalst growth factor 23 (FGF23) is a protein secreted in the plasma by bone cells. FGF23 controls phosphate and calcitriol plasma concentration. Its main physiological targets are the kidney and the parathyroid gland. Its production is stimulated by phosphate intake and plasma calcitriol levels. FGF23 binds a receptor at the cell surface that is composed by the association of a FGF receptor with the protein Klotho. Klotho expression is restricted to few organs including the kidney and the parathyroid gland. Klotho, which is expressed at the cell surface, can also be released in the plasma after an enzymatic cleavage. The role of the circulating form of Klotho is unknown. In addition to its role as a co-receptor Klotho may control the stability of the renal sodium phosphate transporter NPT2a and the calcium channel TRPV5 via enzymatic properties. FGF23 or Klotho gene disruption in mice leads to similar phenotypes except for the levels of FGF23, undetectable or increased respectively. FGF23 plasma concentration rises from the early stage of renal insufficiency to prevent plasma phosphate concentration from increasing. In parallel Klotho production seems to diminish. These modifications trigger the secondary hyperparathyroidism observed in renal insufficiency. The increase in FGF23 concentration and the decrease in Klotho levels are associated in animals and in human as well to an augmentation of mortality especially from cardiovascular causes and to heart modification: hypertrophy or dysfunction.