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Type I membrane Klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. (Metabola bensjukdomar, fosfatmetabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
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2008 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 10, 4152-4157 p.Article in journal (Refereed) Published
Abstract [en]

Context: The type I membrane protein Klotho was recently shownto mediate PTH secretion in parathyroid cells in response tolow extracellular calcium. In contrast, Klotho inhibits PTHsecretion indirectly through the action of fibroblast growthfactor-23. Abnormal Klotho expression in parathyroid disordersremains to be elucidated.

Objective: The aim of the study was to determine: 1) Klothoexpression in parathyroid adenomas from patients with primaryhyperparathyroidism (pHPT) compared to normal tissue; and 2)its relation to the serum calcium and PTH levels.

Design: Surgically removed parathyroid glands (n = 40) and fournormal parathyroid tissue specimens were analyzed for KlothomRNA and protein levels by quantitative real-time PCR and immunohistochemistry.In vitro effects of calcium on Klotho mRNA expression were studiedin bovine parathyroid cells.

Results: Klotho mRNA levels were significantly decreased (n= 23) or undetectable (n = 17) in parathyroid adenomas comparedto normal tissues (P < 0.001). Reduced Klotho protein expressionwas confirmed by immunohistochemistry. Klotho mRNA levels wereinversely correlated to serum calcium (r = –0.97; P <0.0001), and calcium dose-dependently decreased Klotho mRNAexpression in normal parathyroid cells in vitro (P < 0.01).Serum calcium was the only significant marker of Klotho expressionin multivariate analysis with calcium, phosphate, PTH, and adenomaweight as independent variables.

Conclusions: Parathyroid Klotho expression is decreased or undetectablein pHPT. We provide evidence that 1) serum calcium is stronglyassociated with parathyroid Klotho expression in pHPT; and 2)abnormal PTH secretion in hypercalcemic pHPT subjects is mediatedby Klotho-independent mechanisms.

Place, publisher, year, edition, pages
2008. Vol. 93, no 10, 4152-4157 p.
Keyword [en]
Klotho, Fibroblast growth factor-23, FGF23, FGF-23, pHPT, adenoma, primary hyperparathyroidism, calcium
National Category
Endocrinology and Diabetes
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-107367DOI: 10.1210/jc.2008-0564ISI: 000259903700071OAI: oai:DiVA.org:uu-107367DiVA: diva2:228954
Note

Björklund and Krajisnik contributed equally to this work.

Available from: 2009-08-12 Created: 2009-08-08 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Fibroblast growth factor-23 and Klotho in bone/mineral and parathyroid disorders
Open this publication in new window or tab >>Fibroblast growth factor-23 and Klotho in bone/mineral and parathyroid disorders
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fibroblast growth factor-23 (FGF23) is a novel, bone-produced hormone that regulates renal phosphate (Pi) reabsorption and calcitriol metabolism. Disorders of mineral and bone metabolism, such as autosomal dominant hypophosphatemic rickets (ADHR) and hyperostosis-hyperphosphatemia syndrome (HHS), witness the importance of well-balanced serum levels of FGF23. Patients with chronic kidney disease (CKD) are highly morbid due to Pi retention/hyperphosphatemia and calcitriol deficiency, which lead to elevated serum levels of parathyroid hormone (PTH) and secondary hyperparathyroidism (sHPT). As a response to hyperphosphatemia, CKD patients have also remarkably high serum FGF23 levels, which are associated with cardiovascular risk factors and increased mortality in CKD. The overall aim of this dissertation was to discern a possible role of FGF23 in parathyroid biology. Our in vitro experiments on isolated bovine parathyroid cells demonstrate that FGF23 directly and dose-dependently suppresses the PTH production and secretion, while increasing the expression of the 25-hydroxyvitamin D3-activating enzyme 1α-hydroxylase. We investigated possible expressional changes in the FGF23 receptor co-factor Klotho in hyperparathyroid disorders and found that Klotho expression is decreased or absent and inversely correlated to serum calcium (Ca) in adenomas of primary HPT (pHPT). In the hyperplastic parathyroid glands of sHPT, Klotho expression declines in parallel with the kidney function and correlates with the glomerular filtration rate. Moreover, Klotho expression is suppressed by Ca and FGF23, increased by calcitriol, but unaffected by Pi and PTH in vitro. Finally, we identified a novel missense mutation in the gene encoding GALNT3, which is normally involved in the post-translational glycosylation of FGF23, as the cause of aberrant FGF23 processing in a patient with HHS. In summary, we provide evidence for a novel bone/parathyroid axis in which FGF23 functions as a direct, negative regulator of the PTH production. High extracellular Ca is a major determinant of the Klotho expression in pHPT, whereas the Klotho levels in sHPT may be attributed to a combination of the high FGF23 and Ca, and low calcitriol levels associated with CKD. Hence, the decreased Klotho expression in sHPT could explain the concomitantly high FGF23 and PTH levels, as well as the failure of FGF23 to prevent or mitigate the development of sHPT in CKD.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 475
Keyword
calcitriol, chronic kidney disease, CKD, chronic renal failure, fibroblast growth factor 23, fibroblast growth factor-23, FGF23, FGF-23, GalNac-T3, GALNT3, GFR, hyperostosis-hyperphosphatemia syndrome, HHS, Klotho, parathyroid hormone, PTH, hyperparathyroidism, pHPT, sHPT, uremic, vitamin D3
National Category
Endocrinology and Diabetes
Research subject
Internal Medicine
Identifiers
urn:nbn:se:uu:diva-107456 (URN)978-91-554-7590-1 (ISBN)
Public defence
2009-09-26, Hörsalen, D1, Klinisk mikrobiologi, Dag Hammarskjölds väg 17, Uppsala, 09:30 (Swedish)
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Available from: 2009-09-03 Created: 2009-08-12 Last updated: 2009-10-02Bibliographically approved

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Björklund, PeymanÅkerström, GöranWestin, Gunnar

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