Activation of FGF-23 Mediated Vitamin D Degradative Pathways by Cholecalciferol

Alshayeb, Hala M.; Showkat, Arif; Wall, Barry M.; Gyamlani, Geeta; David, Véronique; Quarles, L. Darryl

doi:10.1210/jc.2014-1308

Cited by 25 publications

(17 citation statements)

References 36 publications

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“…This finding was consistent with the previous 5 cohort and clinical trials that observed a wide range of eGFRs [36,38,39]. Higher FGF-23 concentrations were associated with a significantly higher slope and a significantly higher mean 24,25(OH) 2 D concentration of 20 ng/ml in the MESA study (Multi-Ethnic Study of Atherosclerosis; mean eGFR 78.3 ml/min/1.73 m 2 ) [39].…”

Section: Discussionsupporting

confidence: 90%

“…Thus, it is possible that the effect of FGF-23 on vitamin D levels should be more evident in that patient population. Although previous studies demonstrated significant associations between serum FGF-23 and 1,25(OH) 2 D in subjects with a normal kidney function (eGFR ≥60 ml/min/1.73 m 2 ), confounding factors, including diabetes mellitus, urinary abnormality, medications, such as phosphate binders, and vitamin D were not completely excluded [36,37,38,39]. Furthermore, previous studies did not examine the association between serum FGF-23 and eGFR in subjects with their GFR critically restricted above 60 ml/min/1.73 m 2 [5,40].…”

Section: Discussionmentioning

confidence: 99%

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Fibroblast Growth Factor-23 and Vitamin D Metabolism in Subjects with eGFR ≥60 ml/min/1.73 m<sup>2</sup>

Nakatani

Tsugawa

et al. 2015

Nephron

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Background/Aims: Fibroblast growth factor (FGF)-23 and parathyroid hormone (PTH) are both potent phosphaturic hormones. Since they exert opposite effects on vitamin D metabolism, the measurement of 3 vitamin D metabolites; 25-hydroxyvitamin D (25-OH-D), 1,25-dihydroxyvitamin D (1,25(OH)₂D), and 24,25-dihydroxyvitamin D (24,25(OH)₂D), allows the distinction of the effects of FGF-23 from those of PTH. The aim of this study was to elucidate which factor, FGF-23 or PTH, plays a more important role in the regulation of vitamin D metabolites in subjects with estimated glomerular filtration (eGFR) ≥60 ml/min/1.73 m². Methods: Subjects with eGFR ≥60 ml/min/1.73 m² (n = 20) were enrolled and their serum levels of FGF-23, intact PTH, and vitamin D metabolites were determined. Results: Serum FGF-23 correlated inversely with 1,25(OH)₂D (r = -0.717, p = 0.0004) and the 1,25(OH)₂D/25-OH-D ratio (r = -0.518, p = 0.019), compared with a significant positive correlation between serum intact PTH and the 1,25(OH)₂D/25-OH-D ratio (r = 0.562, p = 0.010). Multiple regression analyses revealed serum FGF-23 as a significant factor that was associated with serum 1,25(OH)₂D (β = -0.593, p = 0.018), 1,25(OH)₂D/25-OH-D ratio (β = -0.521, p = 0.025), and the 24,25(OH)₂D/1,25(OH)₂D ratio (β = 0.632, p = 0.008), and intact PTH as a significant factor associated with the 1,25(OH)₂D/25-OH-D ratio (β = 0.445, p = 0.028). Conclusions: This study demonstrated that, even in subjects with eGFR ≥60 ml/min/1.73 m², FGF-23 might play an important role in the regulation of vitamin D metabolism. In addition to the established role of PTH, the association between FGF-23 and indices of vitamin D metabolism suggested the potential role of FGF-23 on phosphate metabolism in such patients.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-23 and Vitamin D Metabolism in Subjects with eGFR ≥60 ml/min/1.73 m<sup>2</sup>

Nakatani

Tsugawa

et al. 2015

Nephron

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“…On the other hand, in the setting of vitamin D deficiency and low calcium, FGF-23 is suppressed, which along with increments in PTH, maximizes 1,25(OH) 2 D production, which in turn, increases gastrointestinal calcium and phosphate absorption. In this setting, elevation of FGF-23 may define a threshold for correcting vitamin D deficiency, which occurs a 25(OH)D levels of 20 ng/ml, which is lower than current levels of vitamin D sufficiency [74]. …”

Section: Fgf-23 Is a Counter-regulatory Hormone For The Pleiotropic Amentioning

confidence: 99%

Multiple faces of fibroblast growth factor-23

Han

Quarles²

2016

Current Opinion in Nephrology and Hypertension

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Purpose of the review This review examines therole of FGF-23 in mineral metabolism, innate immunity and adverse cardiovascular outcomes. Recent findings FGF-23, produced by osteocytes in bone, activates FGFR/α-Klotho complexes in the kidney. The resulting bone-kidney axis coordinates renal phosphate reabsorption with bone mineralization, and creates a counter-regulatory feedback loop to prevent vitamin D toxicity. FGF-23 acts to counter-regulate the effects of Vitamin D on innate immunity and cardiovascular responses. FGF-23 is ectopically expressed along with α-Klotho in activated macrophages, creating a pro-inflammatory paracrine signaling pathway that counters the anti-inflammatory actions of vitamin D. FGF-23 also inhibits ACE2 expression and increases sodium reabsorption in the kidney, leading to hypertension and left ventricular hypertrophy. Finally, FGF-23 is purported to cause adverse cardiac and impair neutrophil responses through activation of FGFRs in the absence of α-Klotho. While secreted forms of α-Klotho have FGF-23- independent effects, the possibility of α-Klotho-independent effects of FGF-23 is controversial and requires additional experimental validation. Summary FGF-23 participates in a bone-kidney axis regulating mineral homeostasis, proinflammatory paracrine macrophage signaling pathways, and in a bone-cardio-renal axis regulating hemodynamics that counteract the effects of Vitamin D.

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“…It also impairs formation of calcitriol and decreases PTH mRNA in the parathyroid glands [ 2 ]. In contrast, increasing levels of calcitriol stimulate the secretion of FGF23 [ 3 ]. While this cause and effect relationship is not yet established, elevated serum concentrations of FGF23 are associated with increased mortality in hemodialysis patients [ 4 ] and patients with stable coronary artery disease [ 5 , 6 ] and are furthermore related to progression of left ventricular hypertrophy and renal disease as well as increased fat mass and dyslipidemia in elderly patients [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%