Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion

• Published in: PLoS genetics 2013-12, Vol.9 (12), p.e1003975
• Main Authors: Olauson, Hannes, Lindberg, Karolina, Amin, Risul, Sato, Tadatoshi, Jia, Ting, Goetz, Regina, Mohammadi, Moosa, Andersson, Göran, Lanske, Beate, Larsson, Tobias E
• Format: Article
• Language: English
• Subjects: Animals; Bone density; Calcineurin; Calcineurin - metabolism; Calcineurin Inhibitors; Calcium - blood; Cyclosporine - pharmacology; Endocrine system; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Gene expression; Gene Expression Regulation - drug effects; Genetic aspects; Genetic research; Health aspects; Hormones; Humans; Hyperparathyroidism; Kidney - metabolism; Medicin och hälsovetenskap; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Parathyroid Glands - metabolism; Parathyroid Hormone - blood; Parathyroid Hormone - genetics; Physiological aspects; Rodents; Sequence Deletion; Signal Transduction - genetics; Statistical analysis; Vitamin D - metabolism
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003975

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.