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Fibroblast growth factor-23 and Klotho in bone/mineral and parathyroid disorders
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- Krajisnik, Tijana, 1981- (author)
- Uppsala universitet,Medicin,Metabola Bensjukdomar, Fosfatmetabolism
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- Larsson, Tobias E., MD, PhD (thesis advisor)
- Uppsala universitet,Medicin
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- Jonsson, Kenneth B., MD, PhD (thesis advisor)
- Uppsala universitet,Ortopedi
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- ISBN 9789155475901
- Uppsala : Acta Universitatis Upsaliensis, 2009
- English 72 s.
- Series: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 475
- Doctoral thesis (other academic/artistic)
Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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
- Endocrinology
- Endokrinologi
- Internal Medicine
- invärtesmedicin
Publication and Content Type
- vet (subject category)
- dok (subject category)
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