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Fibroblast Growth Factor Signaling in Development and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 July 2019) | Viewed by 31260

Special Issue Editors

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Interests: inflammatory lung diseases; aging; fibroblast growth factor signaling; klotho; cystic fibrosis; chronic obstructive pulmonary disease; pulmonary vascular remodeling; fibroblast growth factor 23
Special Issues, Collections and Topics in MDPI journals
Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
Interests: glycobiology; pulmonary vascular disease; fibroblast growth factor signalling; vascular remodelling; vascular smooth muscle cells; and pulmonary hypertension
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The fibroblast growth factor (FGF) family comprises 23 members, which have various pleiotropic biological functions, including roles in development and disease. FGFs bind to and activate one of four highly conserved transmembrane tyrosine kinases receptors (FGFRs) that induce various intracellular signaling pathways. FGFs also act in concert with heparin, heparan sulfate proteoglycans, and/or klotho to activate the FGFRs, which induce pleiotropic cellular responses.

This Issue of the International Journal of Molecular Sciences will focus on “Fibroblast Growth Factor Signaling in Development and Disease”, such as new insights into FGF signaling and how they contribute to known or novel pathways in development and different diseases. While current data shows the importance of FGFs in different physiological and pathological cellular processes, new data is emerging for the potential of inhibition or modulation of FGF signaling as targets for future therapeutical options in various disease states. Furthermore, several cofactors or mediators as well as crosstalk pathways have been shown to impact FGF signaling and submissions on these phenomena, and their contributions are welcome for this Special Issue.

Dr. Stefanie Krick
Dr. Jarrod Barnes
Guest Editors

Manuscript Submission Information

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Keywords

  • fibroblast growth factor
  • fibroblast growth factor receptors
  • klotho
  • signal transduction
  • mitogen activated protein kinase
  • phopholipase C
  • development
  • inflammation

Published Papers (7 papers)

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Editorial

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5 pages, 217 KiB  
Editorial
Fibroblast Growth Factor Signaling in Development and Disease
by Seth Bollenbecker, Jarrod W. Barnes and Stefanie Krick
Int. J. Mol. Sci. 2023, 24(11), 9734; https://doi.org/10.3390/ijms24119734 - 04 Jun 2023
Viewed by 656
Abstract
Fibroblast growth factors (FGFs) and their cognate receptors (FGFRs) are important biological molecules with a wide array of pleiotropic functions [...] Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Signaling in Development and Disease)

Research

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16 pages, 3527 KiB  
Article
FGF23-Mediated Activation of Local RAAS Promotes Cardiac Hypertrophy and Fibrosis
by Ineke Böckmann, Jonas Lischka, Beatrice Richter, Jennifer Deppe, Anja Rahn, Dagmar-Christiane Fischer, Jörg Heineke, Dieter Haffner and Maren Leifheit-Nestler
Int. J. Mol. Sci. 2019, 20(18), 4634; https://doi.org/10.3390/ijms20184634 - 18 Sep 2019
Cited by 69 | Viewed by 5321
Abstract
Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed [...] Read more.
Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin–angiotensin–aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced Ngal indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced Tgfb and Ctgf, which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Signaling in Development and Disease)
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10 pages, 831 KiB  
Article
Fibroblast Growth Factor 23 is Associated with a Frequent Exacerbator Phenotype in COPD: A Cross-Sectional Pilot Study
by Swati Gulati, J. Michael Wells, Gisel P. Urdaneta, Kira Balestrini, Isabel Vital, Katherine Tovar, Jarrod W. Barnes, Surya P. Bhatt, Michael Campos and Stefanie Krick
Int. J. Mol. Sci. 2019, 20(9), 2292; https://doi.org/10.3390/ijms20092292 - 09 May 2019
Cited by 14 | Viewed by 2667
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory airway disease punctuated by exacerbations (AECOPD). Subjects with frequent AECOPD, defined by having at least two exacerbations per year, experience accelerated loss of lung function, deterioration in quality of life and increase in mortality. [...] Read more.
Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory airway disease punctuated by exacerbations (AECOPD). Subjects with frequent AECOPD, defined by having at least two exacerbations per year, experience accelerated loss of lung function, deterioration in quality of life and increase in mortality. Fibroblast growth factor (FGF)23, a hormone associated with systemic inflammation and altered metabolism is elevated in COPD. However, associations between FGF23 and AECOPD are unknown. In this cross-sectional study, individuals with COPD were enrolled between June 2016 and December 2016. Plasma samples were analyzed for intact FGF23 levels. Logistic regression analyses were used to measure associations between clinical variables, FGF23, and the frequent exacerbator phenotype. Our results showed that FGF23 levels were higher in frequent exacerbators as compared to patients without frequent exacerbations. FGF23 was also independently associated with frequent exacerbations (OR 1.02; 95%CI 1.004–1.04; p = 0.017), after adjusting for age, lung function, smoking, and oxygen use. In summary, FGF23 was associated with the frequent exacerbator phenotype and correlated with number of exacerbations recorded retrospectively and prospectively. Further studies are needed to explore the role of FGF 23 as a possible biomarker for AECOPD to better understand the pathobiology of COPD and to help develop therapeutic targets. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Signaling in Development and Disease)
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13 pages, 672 KiB  
Article
Plasmatic Klotho and FGF23 Levels as Biomarkers of CKD-Associated Cardiac Disease in Type 2 Diabetic Patients
by Ana Paula Silva, Filipa Mendes, Eduarda Carias, Rui Baptista Gonçalves, André Fragoso, Carolina Dias, Nelson Tavares, Hugo Mendonça Café, Nélio Santos, Fátima Rato, Pedro Leão Neves and Edgar Almeida
Int. J. Mol. Sci. 2019, 20(7), 1536; https://doi.org/10.3390/ijms20071536 - 27 Mar 2019
Cited by 27 | Viewed by 3914
Abstract
Background: Research over the past decade has focused on the role of Klotho as a cardio protective agent that prevents the effects of aging on the heart and reduces the burden of cardiovascular disease CVD. The role of the interaction between fibroblast growth [...] Read more.
Background: Research over the past decade has focused on the role of Klotho as a cardio protective agent that prevents the effects of aging on the heart and reduces the burden of cardiovascular disease CVD. The role of the interaction between fibroblast growth factor 23-(FGF-23)/Klotho in Klotho-mediated actions is still under debate. The main objective was to ascertain the potential use of plasmatic Klotho and FGF23 as markers for CKD-associated cardiac disease and mortality. Methods: This was a prospective analysis conducted in an outpatient diabetic nephropathy clinic, enrolling 107 diabetic patients with stage 2–3 CKD. Patients were divided into three groups according to their left ventricular mass index and relative wall thickness. Results: Multinomial regression analysis demonstrated that low Klotho and higher FGF-23 levels were linked to a greater risk of concentric hypertrophy. In the generalized linear model (GLM), Klotho, FGF-23 and cardiac geometry groups were statistically significant as independent variables of cardiovascular hospitalization (p = 0.007). According to the Cox regression model, fatal cardiovascular events were associated with the following cardiac geometric classifications; eccentric hypertrophy (p = 0.050); concentric hypertrophy (p = 0.041), and serum phosphate ≥ 3.6 mg/dL (p = 0.025), FGF-23 ≥ 168 (p = 0.0149), α-klotho < 313 (p = 0.044). Conclusions: In our population, Klotho and FGF23 are associated with cardiovascular risk in the early stages of CKD. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Signaling in Development and Disease)
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6 pages, 322 KiB  
Article
Normal FGF-21-Serum Levels in Patients with Carnitine Palmitoyltransferase II (CPT II) Deficiency
by Leila Motlagh Scholle, Diana Lehmann, Pushpa Raj Joshi and Stephan Zierz
Int. J. Mol. Sci. 2019, 20(6), 1400; https://doi.org/10.3390/ijms20061400 - 20 Mar 2019
Cited by 5 | Viewed by 2378
Abstract
Fibroblast growth factor 21 (FGF-21) is known to be a biomarker for mitochondrial disorders. An upregulation of FGF-21 in serum and muscle of carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) knock-out mice has been reported. In human CPT II [...] Read more.
Fibroblast growth factor 21 (FGF-21) is known to be a biomarker for mitochondrial disorders. An upregulation of FGF-21 in serum and muscle of carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) knock-out mice has been reported. In human CPT II deficiency, enzyme activity and protein content are normal, but the enzyme is abnormally regulated by malonyl-CoA and is abnormally thermolabile. Citrate synthase (CS) activity is increased in patients with CPT II deficiency. This may indicate a compensatory response to an impaired function of CPT II. In this study, FGF-21 serum levels in patients with CPT II deficiency during attack free intervals and in healthy controls were measured by enzyme linked immunosorbent assay (ELISA). The data showed no significant difference between FGF-21 concentration in the serum of patients with CPT II deficiency and that in the healthy controls. The results of the present work support the hypothesis that in muscle CPT II deficiency, in contrast to the mouse knockout model, mitochondrial fatty acid utilization is not persistently reduced. Thus, FGF-21 does not seem to be a useful biomarker in the diagnosis of CPT II deficiency. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Signaling in Development and Disease)
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Review

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21 pages, 772 KiB  
Review
Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges
by Úrsula Martínez-Garza, Daniel Torres-Oteros, Alex Yarritu-Gallego, Pedro F. Marrero, Diego Haro and Joana Relat
Int. J. Mol. Sci. 2019, 20(19), 4692; https://doi.org/10.3390/ijms20194692 - 21 Sep 2019
Cited by 50 | Viewed by 8872
Abstract
The Fibroblast Growth Factor 21 (FGF21) is considered an attractive therapeutic target for obesity and obesity-related disorders due to its beneficial effects in lipid and carbohydrate metabolism. FGF21 response is essential under stressful conditions and its metabolic effects depend on the inducer factor [...] Read more.
The Fibroblast Growth Factor 21 (FGF21) is considered an attractive therapeutic target for obesity and obesity-related disorders due to its beneficial effects in lipid and carbohydrate metabolism. FGF21 response is essential under stressful conditions and its metabolic effects depend on the inducer factor or stress condition. FGF21 seems to be the key signal which communicates and coordinates the metabolic response to reverse different nutritional stresses and restores the metabolic homeostasis. This review is focused on describing individually the FGF21-dependent metabolic response activated by some of the most common nutritional challenges, the signal pathways triggering this response, and the impact of this response on global homeostasis. We consider that this is essential knowledge to identify the potential role of FGF21 in the onset and progression of some of the most prevalent metabolic pathologies and to understand the potential of FGF21 as a target for these diseases. After this review, we conclude that more research is needed to understand the mechanisms underlying the role of FGF21 in macronutrient preference and food intake behavior, but also in β-klotho regulation and the activity of the fibroblast activation protein (FAP) to uncover its therapeutic potential as a way to increase the FGF21 signaling. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Signaling in Development and Disease)
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30 pages, 1801 KiB  
Review
The Role of Fibroblast Growth Factor 23 in Inflammation and Anemia
by Brian Czaya and Christian Faul
Int. J. Mol. Sci. 2019, 20(17), 4195; https://doi.org/10.3390/ijms20174195 - 27 Aug 2019
Cited by 62 | Viewed by 6835
Abstract
In patients with chronic kidney disease (CKD), adverse outcomes such as systemic inflammation and anemia are contributing pathologies which increase the risks for cardiovascular mortality. Amongst these complications, abnormalities in mineral metabolism and the metabolic milieu are associated with chronic inflammation and iron [...] Read more.
In patients with chronic kidney disease (CKD), adverse outcomes such as systemic inflammation and anemia are contributing pathologies which increase the risks for cardiovascular mortality. Amongst these complications, abnormalities in mineral metabolism and the metabolic milieu are associated with chronic inflammation and iron dysregulation, and fibroblast growth factor 23 (FGF23) is a risk factor in this context. FGF23 is a bone-derived hormone that is essential for regulating vitamin D and phosphate homeostasis. In the early stages of CKD, serum FGF23 levels rise 1000-fold above normal values in an attempt to maintain normal phosphate levels. Despite this compensatory action, clinical CKD studies have demonstrated powerful and dose-dependent associations between FGF23 levels and higher risks for mortality. A prospective pathomechanism coupling elevated serum FGF23 levels with CKD-associated anemia and cardiovascular injury is its strong association with chronic inflammation. In this review, we will examine the current experimental and clinical evidence regarding the role of FGF23 in renal physiology as well as in the pathophysiology of CKD with an emphasis on chronic inflammation and anemia. Full article
(This article belongs to the Special Issue Fibroblast Growth Factor Signaling in Development and Disease)
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