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

Autor: Regina Goetz, Tobias E. Larsson, Karolina Lindberg, Hannes Olauson, Ting Jia, Moosa Mohammadi, Göran Andersson, Beate Lanske, Tadatoshi Sato, Risul Amin
Jazyk: angličtina
Rok vydání: 2013
Předmět:
MAPK/ERK pathway
Cancer Research
030232 urology & nephrology
Parathyroid hormone
Kidney
Fibroblast growth factor
urologic and male genital diseases
Mice
0302 clinical medicine
Vitamin D
Klotho
Genetics (clinical)
Sequence Deletion
0303 health sciences
Calcineurin
3. Good health
medicine.anatomical_structure
Parathyroid Hormone
Cyclosporine
Secondary hyperparathyroidism
hormones
hormone substitutes
and hormone antagonists
Research Article
Signal Transduction
medicine.medical_specialty
lcsh:QH426-470
Calcineurin Inhibitors
Biology
Parathyroid Glands
03 medical and health sciences
Internal medicine
Genetics
medicine
Animals
Humans
Klotho Proteins
Molecular Biology
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Membrane Proteins
Kidney metabolism
medicine.disease
Fibroblast Growth Factors
Fibroblast Growth Factor-23
stomatognathic diseases
lcsh:Genetics
Endocrinology
Gene Expression Regulation
Calcium
Parathyroid gland
Zdroj: PLoS Genetics, Vol 9, Iss 12, p e1003975 (2013)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: 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.
Author Summary Inorganic calcium is a critical element for a diverse range of cellular processes ranging from cell signaling to energy metabolism, and its extracellular concentration is controlled by parathyroid hormone (PTH). Klotho is expressed in parathyroid chief cells and reported to facilitate PTH secretion during hypocalcemia and mediate FGF23 suppression of PTH synthesis and secretion. To dissect the role of parathyroid Klotho in health and disease, we generated parathyroid-specific Klotho knockout mice. The mutant mice had normal serum levels of PTH and calcium. Further, their parathyroid sensitivity to acute fluctuations in serum calcium and response to FGF23 treatment were preserved, and mutant mice developed secondary hyperparathyroidism of similar magnitude as wild-type mice when challenged with renal failure. A previously unknown parathyroid FGF23 signaling pathway involving calcineurin was constitutively activated in the mutant mice, and blocking this pathway abolished FGF23-induced suppression of PTH secretion. Our data challenges the concepts of Klotho as a mandatory factor for the acute hypocalcemic PTH response and decreased Klotho abundance as a pathogenic factor in secondary hyperparathyroidism. Finally, the presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action.
Databáze: OpenAIRE
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