The experimental detection of FGF23 responsiveness in target organs

Abstract Canonical fibroblast growth factor 23 (FGF23) signaling requires FGF receptors (FGFRs), α-Klotho, and heparan sulfate (HS). Dimerization of two stable FGF23–FGFR–Klotho–HS quaternary signaling complexes is necessary to induce signal activation of the intracellular tyrosine kinase component of FGFR. FGF23 activates multiple pathways in various tissues including mitogen-activated protein kinases (MAPKs) pathway. MAPK pathway is crucial for the classical actions of FGF23 in the kidney to regulate phosphate transport and 1,25 dihydroxyvitamin D production. The noncanonical FGF23 signaling pathway is independent of α-Klotho and requires only FGFR4 to activate intracellular signaling. Activation of phospholipase C gamma/calcineurin/nuclear factor of activated T-cell signaling by FGF23 is important in organs that do not express α-Klotho or under pathological conditions causing reduced α-Klotho expression such as chronic kidney disease. In this chapter, we will review tools and models used to study FGF23 signaling and responsiveness in target organs.