Regulation of calcium and phosphate metabolism by inorganic phosphate sensor (type IIc Na/Pi cotransporter)

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Phosphate ions ate critical for normal bone mineralization, and phosphate plays a vital role in a number of other biological processes such as signal transduction, nucleotide metabolism, and enzyme regulation. In the present study, we have cloned a putative inorganic phosphate sensor (type IIc Na/Pi cotransporter) that is expressed in kidney, bone and brain. A novel phosphaturic factor, fibroblast growth factor 23,decreased the expression of inorganic phosphate sensor (type IIc) in the kidney. We demonstrated that klotho and FGF23 functions via a common signaling pathway. FGF23 binds to the klotho/FGF receptor (FGFR) complex with higher affinity than it binds to FGFR or klotho alone. In addition, klotho significantly enhances the ability of FGF23 to induce phosphorylation of an FGF receptor substrate and ERK in various types of cells, suggesting that klotho functions as a cofactor essential for activation of FGF signaling by FGF23. Finally, we demonstrated that FGF23/klotho signaling is necessary to regulate the expression of inorganic phosphate sensor (type IIc) in the kidney and bone.