Olauson, HannesLindberg, KarolinaAmin, RisulSato, TadatoshiJia, TingGoetz, ReginaMohammadi, MoosaAndersson, GöranMannstadt, BeateLarsson, Tobias E.2014-03-112013Olauson, Hannes, Karolina Lindberg, Risul Amin, Tadatoshi Sato, Ting Jia, Regina Goetz, Moosa Mohammadi, Göran Andersson, Beate Lanske, and Tobias E. Larsson. 2013. “Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion.” PLoS Genetics 9 (12): e1003975. doi:10.1371/journal.pgen.1003975. http://dx.doi.org/10.1371/journal.pgen.1003975.1553-7390http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879357Klotho 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.en-USJournal Article2014-03-1110.1371/journal.pgen.1003975