An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk

Fibroblast growth factor-23 (FGF)-23 is a phosphaturic hormone involved in mineral bone metabolism that helps control phosphate homeostasis and reduces 1,25-dihydroxyvitamin D synthesis. Recent data have highlighted the relevant direct FGF-23 effects on the myocardium, and high plasma levels of FGF-23 have been associated with adverse cardiovascular outcomes in humans, such as heart failure and arrhythmias. Therefore, FGF-23 has emerged as a novel biomarker of cardiovascular risk in the last decade. Indeed, experimental data suggest FGF-23 as a direct mediator of cardiac hypertrophy development, cardiac fibrosis and cardiac dysfunction via specific myocardial FGF receptor (FGFR) activation. Therefore, the FGF-23/FGFR pathway might be a suitable therapeutic target for reducing the deleterious effects of FGF-23 on the cardiovascular system. More research is needed to fully understand the intracellular FGF-23-dependent mechanisms, clarify the downstream pathways and identify which could be the most appropriate targets for better therapeutic intervention. This review updates the current knowledge on both clinical and experimental studies and highlights the evidence linking FGF-23 to cardiovascular events. The aim of this review is to establish the specific role of FGF-23 in the heart, its detrimental effects on cardiac tissue and the possible new therapeutic opportunities to block these effects.

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The Complexity of FGF23 Effects on Cardiomyocytes in Normal and Uremic Milieu

Cells ◽

10.3390/cells10051266 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1266

Author(s):

Andreja Figurek ◽

Merita Rroji ◽

Goce Spasovski

Keyword(s):

Chronic Kidney Disease ◽

Heart Disease ◽

Cardiovascular Risk ◽

Current Knowledge ◽

Fibroblast Growth Factor 23 ◽

Mechanisms Of Action ◽

Fibroblast Growth ◽

Normal Kidney ◽

Future Perspectives ◽

Therapeutic Possibilities

Fibroblast growth factor-23 (FGF23) appears to be one of the most promising biomarkers and predictors of cardiovascular risk in patients with heart disease and normal kidney function, but moreover in those with chronic kidney disease (CKD). This review summarizes the current knowledge of FGF23 mechanisms of action in the myocardium in the physiological and pathophysiological state of CKD, as well as its cross-talk to other important signaling pathways in cardiomyocytes. In this regard, current therapeutic possibilities and future perspectives are also discussed.

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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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Clinical Significance of FGF-23 in Patients with CKD

International Journal of Nephrology ◽

10.4061/2011/364890 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 20

Author(s):

Domenico Russo ◽

Yuri Battaglia

Keyword(s):

Ventricular Hypertrophy ◽

Vascular Dysfunction ◽

Left Ventricular ◽

Vitamin D Metabolism ◽

Fgf Receptor ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Phosphate Retention ◽

Fgf 23

FGF23 is a bone-derived hormone that plays an important role in the regulation of phosphate and 1,25-dihydroxy vitamin D metabolism. FGF23 principally acts in the kidney to induce urinary phosphate excretion and suppress 1,25-dihydroxyvitamin D synthesis in the presence of FGF receptor 1 (FGFR1) and its coreceptor Klotho. In patients with chronic kidney disease (CKD), circulating FGF23 levels are progressively increased to compensate for persistent phosphate retention, but this results in reduced renal production of 1,25-dihydroxyvitamin D and leads to hypersecretion of parathyroid hormone. Furthermore, FGF23 is associated with vascular dysfunction, atherosclerosis, and left ventricular hypertrophy. This paper summarizes the role of FGF23 in the pathogenesis of mineral, bone, and cadiovascular disorders in CKD.

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Uraemic Cardiomyopathy in Different Mouse Models

Frontiers in Medicine ◽

10.3389/fmed.2021.690517 ◽

2021 ◽

Vol 8 ◽

Author(s):

Cheng Chen ◽

Caidie Xie ◽

Hanzhang Wu ◽

Lin Wu ◽

Jingfeng Zhu ◽

...

Keyword(s):

Mouse Models ◽

Cardiac Fibrosis ◽

Sham Group ◽

Fibroblast Growth Factor 23 ◽

Structure And Function ◽

Fibroblast Growth ◽

Growth Differentiation Factor 15 ◽

Group 5 ◽

And Function ◽

Fgf 23

Uraemic cardiomyopathy (UCM) is one of the most common complications in chronic kidney disease (CKD). Our aim was to compare characteristics of various UCM mouse models. Mice were assigned to the following groups: the pole ligation group, 5/6 nephrectomy group (5/6Nx), uninephrectomy plus contralateral ischemia followed by reperfusion group (IR), adenine group, and sham group. Mice were sacrificed at 4, 8, and 16 weeks after surgery in the pole ligation, 5/6Nx, and IR groups, respectively. In the adenine group, mice were sacrificed at 16 weeks after the adenine diet. The structure and function of the heart and the expression of fibroblast growth factor 23 (FGF-23) and growth differentiation factor 15 (GDF-15) in hearts were assessed. The mortality in the 5/6 Nx group was significantly higher than that in the pole ligation, IR, and adenine groups. Echocardiogram and histological examination showed cardiac hypertrophy in the adenine,5/6Nx, ligation group, and IR group. In addition, cardiac fibrosis occurred in all CKD modeling groups. Interestingly, cardiac fibrosis was more serious in the IR and adenine groups. FGF-23 expression in sham mice was similar to that in modeling groups; however, the GDF-15 level was decreased in modeling groups. Our results suggest that the four models of UCM show different phenotypical features, molding time and mortality. GDF-15 expression in the hearts of UCM mice was downregulated compared with sham group mice.

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Cardiovascular Effects of Renal Distal Tubule Deletion of the FGF Receptor 1 Gene

Journal of the American Society of Nephrology ◽

10.1681/asn.2017040412 ◽

2017 ◽

Vol 29 (1) ◽

pp. 69-80 ◽

Cited By ~ 14

Author(s):

Xiaobin Han ◽

Jed Ross ◽

Ganesh Kolumam ◽

Min Pi ◽

Junichiro Sonoda ◽

...

Keyword(s):

Transient Receptor Potential ◽

Fibroblast Growth Factor 23 ◽

Receptor Potential ◽

Cardiovascular Effects ◽

Distal Tubule ◽

Left Ventricular ◽

Conditional Knockout ◽

Systemic Hemodynamic ◽

Fgf Receptor ◽

Fgf 23

The bone-derived hormone fibroblast growth factor–23 (FGF-23) activates complexes composed of FGF receptors (FGFRs), including FGFR1, and α-Klotho in the kidney distal tubule (DT), leading to increased sodium retention and hypertension. However, the role of FGFR1 in regulating renal processes linked to hypertension is unclear. Here, we investigated the effects of selective FGFR1 loss in the DT. Conditional knockout (cKO) of FGFR1 in the DT (FGFR1DT-cKO mice) resulted in left ventricular hypertrophy (LVH) and decreased kidney expression of α-Klotho in association with enhanced BP, decreased expression of angiotensin converting enzyme 2, and increased expression of the Na+-K+-2Cl− cotransporter. Notably, recombinant FGF-23 administration similarly decreased the kidney expression of α-Klotho and induced LVH in mice. Pharmacologic activation of FGFR1 with a monoclonal anti-FGFR1 antibody (R1MAb1) normalized BP and significantly attenuated LVH in the Hyp mouse model of excess FGF-23, but did not induce a response in FGFR1DT-cKO mice. The hearts of FGFR1DT-cKO mice showed increased expression of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6), consistent with cardiac effects of soluble Klotho deficiency. Moreover, administration of recombinant soluble Klotho lowered BP in the Hyp mice. Thus, FGFR1 in the DT regulates systemic hemodynamic responses opposite to those predicted by the actions of FGF-23. These cardiovascular effects appear to be mediated by paracrine FGF control of kidney FGFR1 and subsequent regulation of soluble Klotho and TRPC6. FGFR1 in the kidney may provide a new molecular target for treating hypertension.

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Crosstalk between TGF-β and WNT signalling pathways during cardiac fibrogenesis

Acta Biochimica Polonica ◽

10.18388/abp.2018_2635 ◽

2018 ◽

Vol 65 (3) ◽

pp. 341-349 ◽

Cited By ~ 24

Author(s):

Edyta Działo ◽

Karolina Tkacz ◽

Przemysław Błyszczuk

Keyword(s):

Stromal Cells ◽

Cardiac Fibrosis ◽

Cardiac Tissue ◽

Transforming Growth Factor ◽

Current Knowledge ◽

Transforming Growth Factor Β ◽

Cellular Level ◽

Wnt Signalling ◽

Signalling Pathways ◽

Electrical Impulses

Cardiac fibrosis is referred to as an excessive accumulation of stromal cells and extracellular matrix proteins in the myocardium. Progressive fibrosis causes stiffening of the cardiac tissue and affects conduction of electrical impulses, leading to heart failures in a broad range of cardiac conditions. At the cellular level, activation of the cardiac stromal cells and myofibroblast formation are considered as hallmarks of fibrogenesis. At the molecular level, transforming growth factor β (TGF-β) is traditionally considered as a master regulator of the profibrotic processes. More recently, the WNT signalling pathway has also been found to be implicated in the development of myocardial fibrosis. In this review, we summarize current knowledge on the involvement of TGF-β and WNT downstream molecular pathways to cardiac fibrogenesis and describe a crosstalk between these two profibrotic pathways. TGF-β and WNT ligands bind to different receptors and trigger various outputs. However, a growing body of evidence points to cross-regulation between these two pathways. It has been recognized that in cardiac pathologies TGF-β activates WNT/β-catenin signalling, which in turn stabilizes the TGF-β/Smad response. Furthermore both, the non-canonical TGF-β and non-canonical WNT signalling pathways, activate the same mitogen-activated protein kinases (MAPKs): the extracellular signal-regulated kinase (Erk), the c-Jun N-terminal kinases (JNKs) and p38. The cross-talk between TGF-β and WNT pathways seems to play an essential role in switching on the genetic machinery initiating profibrotic changes in the heart. Better understanding of these mechanisms will open new opportunities for development of targeted therapeutic approaches against cardiac fibrosis in the future.

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Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels

American Journal of Nephrology ◽

10.1159/000511658 ◽

2020 ◽

Vol 51 (11) ◽

pp. 871-880

Author(s):

Corey M. Forster ◽

Christine A. White ◽

Mandy E. Turner ◽

Patrick A. Norman ◽

Emilie C. Ward ◽

...

Keyword(s):

Bone Disease ◽

Mineral Metabolism ◽

Early Stage ◽

Fibroblast Growth Factor 23 ◽

Vitamin D Metabolites ◽

Related Protein ◽

Clinical Indicators ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Fgf 23

Background: The Wnt/β-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). Methods: GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. Results: The median [IQR] age was 64 years [53.0–71.0], and the median [IQR] mGFR was 32.6 [21.7–60.6] mL/min. DKK1 decreased (r = 0.6, p < 0.001) and sclerostin increased (r = −0.4, p < 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D3 in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. Conclusion: The results of this study demonstrate opposing trends in Wnt/β-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

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Hypophosphatemic rickets and osteomalacia

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302006000400025 ◽

2006 ◽

Vol 50 (4) ◽

pp. 802-813 ◽

Cited By ~ 22

Author(s):

Hamilton de Menezes Filho ◽

Luiz Claudio G. de Castro ◽

Durval Damiani

Keyword(s):

Current Knowledge ◽

Bone Mineralization ◽

Fibroblast Growth Factor 23 ◽

Hypophosphatemic Rickets ◽

Activating Mutations ◽

Metabolism Regulation ◽

Autosomal Dominant Hypophosphatemic Rickets ◽

Phex Gene ◽

Fgf 23 ◽

Increased Activity

The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing osteomalacia or rickets in children and osteomalacia in adults. X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and tumor-induced osteomalacia are the main syndromes involved in the hypophosphatemic rickets. Although these conditions exhibit different etiologies, there is a common link among them: increased activity of a phosphaturic factor, being the fibroblast growth factor 23 (FGF-23) the most studied one and to which is attributed a central role in the pathophysiology of the hyperphosphaturic disturbances. Activating mutations of FGF-23 and inactivating mutations in the PHEX gene (a gene on the X chromosome that codes for a Zn-metaloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been implicated in the pathogenesis of these disturbances. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal metabolic axis, whose mechanisms of interaction have been poorly understood so far. This paper reviews the current knowledge status concerning the pathophysiology of phosphate metabolism regulation and the pathophysiologic basis of hypophosphatemic rickets. It also analyzes the clinical picture and the therapeutic aspects of these conditions as well.

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FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1

AJP Renal Physiology ◽

10.1152/ajprenal.90742.2008 ◽

2009 ◽

Vol 297 (2) ◽

pp. F282-F291 ◽

Cited By ~ 256

Author(s):

Jyothsna Gattineni ◽

Carlton Bates ◽

Katherine Twombley ◽

Vangipuram Dwarakanath ◽

Michael L. Robinson ◽

...

Keyword(s):

Fibroblast Growth Factor 23 ◽

Serum Phosphorus ◽

Minor Role ◽

Metanephric Mesenchyme ◽

Fgf Receptor ◽

Targeted Deletion ◽

Dihydroxyvitamin D ◽

A Minor ◽

Phosphorus Levels

Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, −3, and −4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3−/− and FGFR4−/− null mice, and in conditional FGFR1−/− mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1−/−, FGFR3−/−, and FGFR4−/− mice and their wild-type counterparts. Administration of FGF23 to FGFR3−/− mice induced hypophosphatemia in these mice (8.0 ± 0.4 vs. 5.4 ± 0.3 mg/dl; p ≤ 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4−/− mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 ± 0.3 vs. 7.6 ± 0.4 mg/dl; p ≤ 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1−/− mice had no effects on serum phosphorus levels (5.6 ± 0.3 vs. 5.2 ± 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.

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Rachitismo ipofosforemico X-linked

Medico e Bambino ◽

10.53126/meb39430 ◽

2020 ◽

Vol 39 (7) ◽

pp. 430-436

Author(s):

Laura Lucchetti ◽

Francesco Emma ◽

Danilo Fintini ◽

Marco Cappa

Keyword(s):

Clinical Symptoms ◽

Fibroblast Growth Factor 23 ◽

Vitamin D Supplementation ◽

Elevated Alkaline Phosphatase ◽

Dihydroxyvitamin D ◽

Igg1 Monoclonal Antibody ◽

Physical Dysfunction ◽

Phex Gene ◽

Fgf 23 ◽

Phosphate Salts

X-linked hypophosphatemia (XLH) is an X-linked disorder with dominant penetration, caused by mutations in the PHEX gene, which encodes for an endopeptidase that is predominantly expressed in osteoblasts, osteocytes and odontoblasts. PHEX mutations cause increased production of fibroblast growth factor 23 (FGF23) that in turn leads to hypophosphatemia by causing inhibition of the renal phosphate reabsorption and of the synthesis of active 1,25-dihydroxyvitamin D. In children XLH is characterised by rickets, bone pain, physical dysfunction, impaired growth, disproportionate short stature, lowerlimb deformities, pathological fractures, dental malposition and dental abscesses. Although phenotype may be variable in severity, early diagnosis and treatment are critical to improve outcome. Laboratory tests show hypophosphatemia associated with hyperphosphaturia and elevated alkaline phosphatase, while parathormone and calcium levels are normal. For decades, patients have been treated with conventional therapy, including active vitamin D supplementation and fractionated daily doses of oral phosphate salts. However, these therapies rarely normalise the phenotype. More recently, burosumab, a recombinant human IgG1 monoclonal antibody against FGF-23, has been introduced for the treatment of XLH. In phase 2 trials, burosumab has been shown to improve significantly clinical symptoms, as well as biological and radiological signs of rickets.

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