Circulating Fibroblast Growth Factor-23 (FGF-23) following vitamin D supplementation in vitamin D insufficiency

Fibroblast growth factor-23 (FGF-23) has been recently identified as playing an important pathophysiological role in phosphate homeostasis and vitamin D metabolism. To elucidate the precise physiological regulation of FGF-23, we characterized the mouse FGF-23 5′-flanking region and analyzed its promoter activity. The 5′-flanking region of the mouse FGF-23 gene contained a TFIID site (TATA box) and several putative transcription factor binding sites, including MZF1, GATA-1 and c-Ets-1 motifs, but it did not contain the typical sequences of the vitamin D response element. Plasmids encoding 554-bp (pGL/−0.6), 364-bp (pGL/−0.4) and 200-bp (pGL/−0.13) promoter regions containing the TFIID element and +1-bp fragments drove the downstream expression of a luciferase reporter gene in transfection assays. We also found that FGF-23 mRNA was expressed in K-562 erythroleukemia cell lines but not in MC3T3-E1, Raji, or Hep G2 human carcinoma cells. Treatment with 1,25-dihydroxyvitamin D3in the presence of high phosphate markedly stimulated pGL/−0.6 activity, but calcium had no effect. In addition, the plasma FGF-23 levels were affected by the dietary and plasma inorganic phosphate concentrations. Finally, the levels of plasma FGF-23 in vitamin D receptor-null mice were significantly lower than in wild-type mice. The presents study demonstrated that vitamin D and the plasma phosphate level are important regulators of the transcription of the mouse FGF-23 gene.

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Effect of a 300 000-IU Loading Dose of Ergocalciferol (Vitamin D2) on Circulating 1,25(OH)2-Vitamin D and Fibroblast Growth Factor-23 (FGF-23) in Vitamin D Insufficiency

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-2790 ◽

2013 ◽

Vol 98 (2) ◽

pp. 550-556 ◽

Cited By ~ 29

Author(s):

C. Turner ◽

N. Dalton ◽

R. Inaoui ◽

I. Fogelman ◽

W. D. Fraser ◽

...

Keyword(s):

Vitamin D ◽

Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Vitamin D Insufficiency ◽

High Dose ◽

Vitamin D2 ◽

Loading Dose ◽

Fibroblast Growth ◽

Fgf 23 ◽

High Dose Vitamin

Abstract Context: Several trials have reported an increased risk of fractures and falls after intermittent high-dose vitamin D. Treatment with loading doses of vitamin D may increase 1,25(OH)2 vitamin D catabolism through changes in calcium/phosphate homeostasis and fibroblast growth factor-23 (FGF-23). Objective: The aim was to determine the effects of high-dose vitamin D on circulating concentrations of 1,25(OH)2 vitamin D and FGF-23 in patients with osteoporosis and vitamin D insufficiency. Design, Setting, Patients, and Intervention: We carried out a prospective study of 45 subjects with vitamin D deficiency/insufficiency treated with a bolus dose of 300 000 IU of vitamin D2 im. Blood samples were obtained at baseline and 1, 2, and 3 months after treatment. Outcome Measures: Changes in 1,25(OH)2-vitamin D and FGF-23 were measured. Results: Loading dose of vitamin D2 increased 1,25(OH)2-vitamin D2 at 3 months, with a mean [SD] of 41 [56] pmol/L at baseline and 162.3 [137.8] pmol/L at 3 months (P < .001). FGF-23 increased significantly at all time points with a peak at 3 months, with percent change from baseline (mean [SEM]) of 50% [48%] at 3 months (P < .01). There was a positive correlation between FGF-23 and serum phosphate (r = 0.36, P = .024) and calcium (r = 0.532, P < .001) and a negative correlation between total 1,25(OH)2-vitamin D and FGF-23 (r = −0.32, P = .036) at 3 months. Conclusions: High-dose vitamin D increases 1,25(OH)2-vitamin D and FGF-23 concentration. Further studies are required to determine whether adjusting vitamin D dose and frequency to minimize increases in FGF-23 may prevent the adverse outcomes associated with high-dose intermittent vitamin D supplementation.

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The effect of vitamin D supplementation on fibroblast growth factor‐23 in patients with chronic kidney disease: A systematic review and meta‐analysis

Phytotherapy Research ◽

10.1002/ptr.7139 ◽

2021 ◽

Author(s):

Elmira Karimi ◽

Sama Bitarafan ◽

Seyed Mohammad Mousavi ◽

Nikan Zargarzadeh ◽

Pari Mokhtari ◽

...

Keyword(s):

Systematic Review ◽

Chronic Kidney Disease ◽

Vitamin D ◽

Growth Factor ◽

Kidney Disease ◽

Fibroblast Growth Factor ◽

Meta Analysis ◽

Fibroblast Growth Factor 23 ◽

Vitamin D Supplementation ◽

Fibroblast Growth

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Fibroblast Growth Factor 23: A Biomarker of Kidney Function Decline

American Journal of Nephrology ◽

10.1159/000488361 ◽

2018 ◽

Vol 47 (4) ◽

pp. 242-250 ◽

Cited By ~ 4

Author(s):

David A. Drew ◽

Ronit Katz ◽

Stephen Kritchevsky ◽

Joachim H. Ix ◽

Michael G. Shlipak ◽

...

Keyword(s):

Older Adults ◽

Vitamin D ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Kidney Function ◽

Fibroblast Growth Factor 23 ◽

Community Dwelling ◽

Fibroblast Growth ◽

Fgf 23 ◽

Kidney Function Decline

Background: Fibroblast growth factor 23 (FGF-23) is a hormone that regulates phosphorus levels and vitamin D metabolism. Previous studies have shown FGF-23 to be a risk factor for incident end-stage renal disease; however, there are less data on the association of FGF-23 with earlier kidney-related outcomes. Methods: Serum FGF-23 was assayed using an intact ELISA assay in 2,496 participants of the Healthy Aging and Body Composition Study, a cohort of well-functioning older adults. Kidney function was estimated by assaying cystatin C at baseline and years 3 and 10. The associations between FGF-23 and decline in kidney function (defined by estimated glomerular filtration rate (eGFR) decline ≥30% or ≥3 mL/min/year) and incident chronic kidney disease (CKD; incident eGFR <60 mL/min/1.73 m2 and ≥1 mL/min/year decline) were evaluated. Models were adjusted for demographics, baseline eGFR, urine albumin/creatinine ratio, comorbidity, and serum calcium, phosphorus, 25(OH) vitamin D and parathyroid hormone. Results: The mean (SD) age was 75 (3) years, with 52% female and 38% black. There were 405 persons with 30% decline, 702 with >3 mL/min/year decline, and 536 with incident CKD. In fully adjusted continuous models, doubling of FGF-23 concentrations was not associated with kidney function decline (OR [95% CI] = 0.98 [0.82–1.19] for ≥30% decline and OR 1.17 [95% CI 1.00–1.37] for ≥3 mL/min/year decline), or incident CKD (incident rate ratio [IRR] 1.05 [95% CI 0.91–1.22]). In adjusted quartile analysis, the highest quartile of FGF-23 was significantly associated with incident CKD (IRR 1.27 [95% CI 1.02–1.58] for highest vs. lowest quartile). Conclusion: Higher FGF-23 concentrations were not consistently associated with decline in kidney function or incident CKD in community-dwelling older adults.

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Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro

AJP Renal Physiology ◽

10.1152/ajprenal.00463.2006 ◽

2007 ◽

Vol 293 (5) ◽

pp. F1577-F1583 ◽

Cited By ~ 189

Author(s):

Farzana Perwad ◽

Martin Y. H. Zhang ◽

Harriet S. Tenenhouse ◽

Anthony A. Portale

Keyword(s):

Gene Expression ◽

Vitamin D ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Signaling Pathway ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Vitamin D Metabolism ◽

Fgf 23 ◽

Dose Dependent

Fibroblast growth factor-23 (FGF-23) is critical to the pathogenesis of a distinct group of renal phosphate wasting disorders: tumor-induced osteomalacia, X-linked hypophosphatemia, and autosomal dominant and autosomal recessive hypophosphatemic rickets. Excess circulating FGF-23 is responsible for their major phenotypic features which include hypophosphatemia due to renal phosphate wasting and inappropriately low serum 1,25(OH)2D concentrations. To characterize the effects of FGF-23 on renal sodium-phosphate (Na/Pi) cotransport and vitamin D metabolism, we administered FGF-23(R176Q) to normal mice. A single injection (0.33 μg/g body wt) induced significant hypophosphatemia, 20 and 29% decreases ( P < 0.001) in brush-border membrane (BBM) Na/Pi cotransport at 5 and 17 h after injection, respectively, and comparable decreases in the abundance of type IIa Na/Pi cotransporter protein in BBM. Multiple injections (6, 12, and 24 μg/day for 4 days) induced dose-dependent decreases (38, 63, and 75%, respectively) in renal abundance of 1α-hydroxylase mRNA ( P < 0.05). To determine whether FGF-23(R176Q) exerts a direct action on 1α-hydroxylase gene expression, we examined its effects in cultured human (HKC-8) and mouse (MCT) renal proximal tubule cells. FGF-23(R176Q) (1 to 10 ng/ml) induced a dose-dependent decrease in 1α-hydroxylase mRNA with a maximum suppression of 37% ( P < 0.05). Suppression was detectable after 6 h of exposure and maximal after 21 h. In MCT cells, FGF-23(R176Q) suppressed 1α-hydroxylase mRNA and activated the ERK1/2 signaling pathway. The MAPK inhibitor PD98059 effectively abolished FGF-23-induced suppression of 1α-hydroxylase mRNA by blocking signal transduction via ERK1/2. These novel findings provide evidence that FGF-23 directly regulates renal 1α-hydroxylase gene expression via activation of the ERK1/2 signaling pathway.

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Fibroblast Growth Factor 23 and Disordered Vitamin D Metabolism in Chronic Kidney Disease: Updating the “Trade-off” Hypothesis: Figure 1.

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.02640310 ◽

2010 ◽

Vol 5 (9) ◽

pp. 1710-1716 ◽

Cited By ~ 91

Author(s):

Orlando M. Gutiérrez

Keyword(s):

Chronic Kidney Disease ◽

Vitamin D ◽

Growth Factor ◽

Kidney Disease ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Vitamin D Metabolism ◽

Trade Off

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Increased Levels of sRAGE in Diabetic CKD-G5D Patients: A Potential Protective Mechanism against AGE-Related Upregulation of Fibroblast Growth Factor 23 and Inflammation

Mediators of Inflammation ◽

10.1155/2017/9845175 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Elena Dozio ◽

Valentina Corradi ◽

Elena Vianello ◽

Elisa Scalzotto ◽

Massimo de Cal ◽

...

Keyword(s):

Cardiovascular Risk ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Cardiac Remodeling ◽

Glycated Albumin ◽

Fibroblast Growth Factor 23 ◽

Protective Mechanism ◽

Fibroblast Growth ◽

Increased Risk ◽

Fgf 23

Advanced glycation end products (AGEs) may induce cardiac remodeling in kidney disease by promoting fibroblast growth factor 23 (FGF-23) expression. Since AGEs are increased in diabetes mellitus (DM), our first aim was to evaluate the existence of any potential association between AGEs, FGF-23, inflammation, and increased cardiovascular risk in DM patients on dialysis (CKD-G5D). Secondarily, we explored the potential role of the soluble receptor for AGEs (sRAGE) as a marker of heart failure. Levels of glycated albumin (GA), sRAGE, c-terminal FGF-23 (cFGF-23), brain natriuretic peptide (BNP), and inflammatory mediators were compared between DM and non-DM CKD-G5D patients. The levels of sRAGE, cFGF-23, BNP, and proinflammatory markers were over the ranges of normality in both DM and non-DM groups. Only GA and sRAGE levels were increased in DM compared to non-DM patients. Plasma levels of sRAGE and CRP were the only independent predictors of BNP concentration. In conclusion, in DM CKD-G5D patients, sRAGE appeared to be a marker of cardiac remodeling. Indeed, its increase could be a potential protective mechanism against the increased risk of cardiovascular complications related to AGEs and inflammation. The causal relationship between sRAGE and cardiovascular risk in these patients needs to be further confirmed by mechanistic studies.

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