Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion

Klotho acts as a co-receptor for and dictates tissue specificity of circulating fgf23. fgf23 inhibits pth secretion,and reduced klotho abundance is considered a pathogenic factor in renal secondary hyperparathyroidism. to dissect the role of parathyroid gland resident klotho in health and disease,we generated mice with a parathyroid-specific klotho deletion (pth-kl-/-). pth-kl-/- mice had a normal gross phenotype and survival; normal serum pth and calcium; unaltered expression of the pth gene in parathyroid tissue; and preserved pth response and sensitivity to acute changes in serum calcium. their pth response to intravenous fgf23 delivery or renal failure did not differ compared to their wild-type littermates despite disrupted fgf23-induced activation of the mapk/erk pathway. importantly,calcineurin-nfat signaling,defined by increased mcip1 level and nuclear localization of nfatc2,was constitutively activated in pth-kl-/- mice. treatment with the calcineurin-inhibitor cyclosporine a abolished fgf23-mediated pth suppression in pth-kl-/- mice whereas wild-type mice remained responsive. similar results were observed in thyro-parathyroid explants ex vivo. collectively,we present genetic and functional evidence for a novel,klotho-independent,calcineurin-mediated fgf23 signaling pathway in parathyroid glands that mediates suppression of pth. the presence of klotho-independent fgf23 effects in a klotho-expressing target organ represents a paradigm shift in the conceptualization of fgf23 endocrine action. © 2013 olauson et al.