Circulating αKlotho influences phosphate handling by controlling FGF23 production.

The FGF23 coreceptor alpha Klotho (alpha KL) is expressed as a membrane-bound protein (mKL),that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytoic cleavage product of mKL (cKL). Previously, a patient With increased Plasma cKL as the result of a translocation [t(9;13)] in the alpha KLOTHO (KL) gene presented with rickets and a complex end-nth:life profile,including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, Mite were treated with an adeno-associated virus producing cKL. The treated groups dose-dependent: hypophosphatemia and hypocalcemia, with markedly elevated-FGF23 (38 to 456 fold). The animals also mani-fested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and-was FGFR dependent These results demonstrate that cKL potently stimulates FGF23 production in vivo,Which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of alpha KL and FGF23 in disorders of phosphite handling and biomineralization.