title: Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion.
abstract: 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.
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hannes
authors.initials: H
authors.lastname: Olauson
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karolina
authors.initials: K
authors.lastname: Lindberg
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Risul
authors.initials: R
authors.lastname: Amin
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ting
authors.initials: T
authors.lastname: Jia
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Regina
authors.initials: R
authors.lastname: Goetz
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, United States of America.
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.affiliation: Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden ; Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Tobias E
authors.initials: TE
authors.lastname: Larsson
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000378:metabolism; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010280:Parathyroid Glands / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics*; D014807:Vitamin D / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C418622:Klb protein, mouse; D008565:Membrane Proteins; D010281:Parathyroid Hormone; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D016572:Cyclosporine; D019703:Calcineurin; D000090265:Klotho Proteins; D002118:Calcium