Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease

Kazuki, Kenichi; Takeshita, Ai; Furushima, Kaoru; Miyajima, Masayasu; Hatamura, Ikuji; Kuro‐o, Makoto; Furuta, Yasuhide; Sakaguchi, Kazushige

doi:10.1038/srep40534

Cited by 46 publications

(32 citation statements)

References 43 publications

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“…An action through CaSR is dominant for regulation of PTH secretion, but Klotho has an adjuvant role in this regulation that may be particularly important when CaSR function is inhibited . Furthermore, persistent exposure to FGF23 has been shown to promote parathyroid cell proliferation and PTH secretion indicating that FGF23 might be a promoter for PTH . These findings demonstrate the complexity of the involvement of FGF23 in PTH regulation.…”

Section: Pathogenesis Of Shptmentioning

confidence: 90%

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

2018

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The classic pathogenesis of secondary hyperparathyroidism (SHPT) began with the trade‐off hypothesis based on parathyroid hormone hypersecretion brought about by renal failure resulting from a physiological response to correct metabolic disorder of calcium, phosphorus, and vitamin D. In dialysis patients with failed renal function, physiological mineral balance control by parathyroid hormone through the kidney fails and hyperparathyroidism progresses. In this process, many significant genetic findings have been established. Abnormalities of Ca‐sensing receptor and vitamin D receptor are associated with the pathogenesis of SHPT, and fibroblast growth factor 23 has also been shown to be involved in the pathogenesis. Vitamin D receptor activators (VDRAs) are widely used for treatment of SHPT. However, VDRAs have calcemic and phosphatemic effects that limit their use to a subset of patients, and calcimimetics have been developed as alternative drugs for SHPT. Hyperphosphatemia also affects progression of SHPT, and control of hyperphosphatemia is, therefore, thought to be fundamental for control of SHPT. Currently, a combination of a VDRA and a calcimimetic is recognized as the optimal strategy for SHPT, and for other outcomes such as reduced cardiovascular disease and improved survival. The latest findings on the pathogenesis and treatment of SHPT are summarized in this review.

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Section: Pathogenesis Of Shptmentioning

confidence: 90%

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

2018

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“…Mean BMI was 33 ± 6 kg/ m 2 and in the study population 61% of the patients had a BMI above 30 kg/m 2 . Median duration of diabetes was 11 [7][8][9][10][11][12][13][14][15][16][17][18] years, and the glucose values of the patients were tolerably regulated with a mean HbA 1c of 57 ± 12 mmol/ mol. The majority used insulin (64%).…”

Section: Study Populationmentioning

confidence: 99%

“…Chronic kidney disease (CKD) is accompanied by pronounced changes in calcium and phosphate metabolism . Some key features are a tendency towards phosphate retention, resulting in an increased secretion of the phosphaturic peptide hormone fibroblast growth factor 23 (FGF23) and an increase in plasma parathyroid hormone (PTH) concentrations . The latter results in increased bone turnover and therefore stimulates the release of phosphate and calcium from the bones into the circulation .…”

Section: Introductionmentioning

confidence: 99%

“…8,9 Some key features are a tendency towards phosphate retention, 10 resulting in an increased secretion of the phosphaturic peptide hormone fibroblast growth factor 23 (FGF23) 11,12 and an increase in plasma parathyroid hormone (PTH) concentrations. 13,14 The latter results in increased bone turnover and therefore stimulates the release of phosphate and calcium from the bones into the circulation. 6,11 As the plasma calcium concentration is under tight regulation, this increased bone turnover does not result in hypercalcemia.…”

Section: Introductionmentioning

confidence: 99%

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Correlations between plasma strontium concentration, components of calcium and phosphate metabolism and renal function in type 2 diabetes mellitus

Berkhof

Gant

Maatman

et al. 2018

Eur J Clin Investigation

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We found an independent inverse association between eGFR and plasma Sr concentration and an independent association between plasma Sr concentration and plasma FGF23 concentration, a marker of deranged calcium and phosphate metabolism. Further research is needed to determine the mechanisms behind these associations and the impact of an elevation in plasma Sr concentration on bone mineralization and calcification.

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“…On the other hand, the parathyroid glands are also endowed with FGF23 receptors that require the co-receptor Klotho for being functionally active. 4 Thus, PTH secretion has a complex regulation being downregulated by the stimulation of the VDR and by short-term exposure to FGF23 but stimulated by long-term exposure to high FGF23. 2 However, these short-term experimental data should be interpreted in a wider context considering observations in FGF receptor 1-4 gene-knockout models showing that FGF23 is a long-term inducer of parathyroid cell proliferation and PTH secretion.…”

Section: Introductionmentioning

confidence: 99%

FGF23 and the PTH response to paricalcitol in chronic kidney disease

D’Arrigo

Pizzini

Cutrupi

et al. 2020

Eur J Clin Investigation

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Background:The parathyroid glands are endowed both with receptors responsive to FGF23 and to 1,25 vitamin D. Vitamin D receptor (VDR) activation, besides lowering PTH, also raises serum FGF23. FGF23 has been implicated in parathyroid resistance to VDR activation but the issue has never been investigated in predialysis CKD patients. Methods: In the Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) study (NCT01680198), a 12-week randomized trial in stage G3-4 CKD patients (placebo n = 44 and paricalcitol n = 44), we measured PTH and the active form of FGF23 with no missing value across the trial. Results: At baseline, serum FGF23 and PTH were inter-related (r = .54, P < .01).Paricalcitol reduced serum PTH (−75.1 pg/mL, 95% CI: −90.4 to −59.8; P < .001) and increased FGF23 (+107 pg/mL, 95% CI: 44-170 pg/mL, P = .001). Changes in the Ca × P product in response to paricalcitol were closely related to simultaneous FGF23 changes in an analysis adjusted for changes in serum calcium and phosphate (P < .001). Of note, baseline FGF23, appropriately adjusted for baseline PTH, was unrelated with the PTH response to paricalcitol (r = −.06, P = .72). Placebo did not change neither PTH nor FGF23. Conclusion: Serum FGF23 and PTH are inter-related and changes in the Ca × P product induced by paricalcitol per se correlate with the FGF23 response to this drug.Independently of serum FGF23, the parathyroid glands of patients with moderate to severe CKD maintain an intact ability to respond to VDR activation. K E Y W O R D SCKD, FGF23, paricalcitol, PTH, Vitamin D, Vitamin D receptor activation

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Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease

Cited by 46 publications

References 43 publications

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment

Correlations between plasma strontium concentration, components of calcium and phosphate metabolism and renal function in type 2 diabetes mellitus

FGF23 and the PTH response to paricalcitol in chronic kidney disease

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