Role Of Fibroblast Growth Factor Research Articles

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COVER PHOTOGRAPH: Snapshot of a secondary septum during alveologenesis. From: Therapeutic and pathological roles of fibroblast growth factors in pulmonary diseases; Elie El Agha, Werner Seeger and Saverio Bellusci; Developmental Dynamics 246:235–244.Read the full article at DOI: 10.1002/dvdy.24468

FIBROBLAST GROWTH FACTOR 23 AS NOVEL BIOMARKER FOR EARLY RISK STRATIFICATION AFTER ST-ELEVATION MYOCARDIAL INFARCTION

Objective Adverse left ventricular (LV) remodelling is the major determinant of heart failure and mortality in survivors of ST-elevation myocardial infarction (STEMI). The role of fibroblast growth factor 23 (FGF-23) for LV remodelling prediction after STEMI is unknown. We therefore aimed to investigate the relation between circulating FGF-23 and LV remodelling following revascularised STEMI. Methods In this prospective observational study, we included 88 consecutive patients with STEMI treated by primary percutaneous coronary intervention. FGF-23 concentrations were measured 2 (IQR: 2–2) days after symptom onset. Cardiac magnetic resonance was performed 2 (IQR: 1–3) days as well as 4 (IQR: 4–5) months after infarction to evaluate LV remodelling, defined as ≥20% increase in LV end-diastolic volume. Results Levels of FGF-23 were significantly higher in patients who developed LV remodelling (n=11, 13%) as compared with those without LV remodelling (152.6 (102.5–241.3) vs 75.8 (58.6–105.4) relative units per millilitre, p=0.002). The association between FGF-23 and LV remodelling remained significant (OR: 14.1, 95% CI 2.8 to 70.9; p=0.001) after adjustment for biomarkers reflecting myocardial necrosis (high-sensitivity cardiac troponin T (hs-cTnT)), myocardial stress (N-terminal pro B-type natriuretic peptide (NT-proBNP)) and inflammatory state (high-sensitivity C reactive protein (hs-CRP)). Moreover, a multimarker approach adding FGF-23 to the established LV remodelling-predictive biomarkers (hs-cTnT, NT-proBNP and hs-CRP) led to a net reclassification improvement of 0.92 (95% CI 0.44 to 1.41, p Conclusions Circulating FGF-23 is independently associated with LV remodelling after reperfused STEMI. A comprehensive multimarker strategy that includes FGF-23 provides incremental prognostic value for prediction of LV remodelling.

Analysis of the FGF gene family provides insights into aquatic adaptation in cetaceans

Cetacean body structure and physiology exhibit dramatic adaptations to their aquatic environment. Fibroblast growth factors (FGFs) are a family of essential factors that regulate animal development and physiology; however, their role in cetacean evolution is not clearly understood. Here, we sequenced the fin whale genome and analysed FGFs from 8 cetaceans. FGF22, a hair follicle-enriched gene, exhibited pseudogenization, indicating that the function of this gene is no longer necessary in cetaceans that have lost most of their body hair. An evolutionary analysis revealed signatures of positive selection for FGF3 and FGF11, genes related to ear and tooth development and hypoxia, respectively. We found a D203G substitution in cetacean FGF9, which was predicted to affect FGF9 homodimerization, suggesting that this gene plays a role in the acquisition of rigid flippers for efficient manoeuvring. Cetaceans utilize low bone density as a buoyancy control mechanism, but the underlying genes are not known. We found that the expression of FGF23, a gene associated with reduced bone density, is greatly increased in the cetacean liver under hypoxic conditions, thus implicating FGF23 in low bone density in cetaceans. Altogether, our results provide novel insights into the roles of FGFs in cetacean adaptation to the aquatic environment.

Therapeutic and pathological roles of fibroblast growth factors in pulmonary diseases

Fibroblast growth factors (FGFs) constitute a large family of polypeptides that are involved in many biological processes, ranging from prenatal cell-fate specification and organogenesis to hormonal and metabolic regulation in postnatal life. During embryonic development, these growth factors are important mediators of the crosstalk among ectoderm-, mesoderm-, and endoderm-derived cells, and they instruct the spatial and temporal growth of organs and tissues such as the brain, bone, lung, gut, and others. The involvement of FGFs in postnatal lung homeostasis is a growing field, and there is emerging literature about their roles in lung pathophysiology. In this review, the involvement of FGF signaling in a wide array of lung diseases will be summarized. Developmental Dynamics 246:235-244, 2017. © 2016 Wiley Periodicals, Inc.

Fibroblast growth factor 23 as novel biomarker for early risk stratification after ST-elevation myocardial infarction

ObjectiveAdverse left ventricular (LV) remodelling is the major determinant of heart failure and mortality in survivors of ST-elevation myocardial infarction (STEMI). The role of fibroblast growth factor 23 (FGF-23) for...

Role of fibroblast growth factor 23 in the development of cardiovascular diseases in patients with end-stage renal failure on programmed hemodialysis

To determine the nature of changes in fibroblast growth factor 23 (FGF-23) and other bone mineral metabolism parameters detectable in the blood of patients with end-stage chronic renal failure (CRF) and to analyze their links to the development of cardiovascular events in uremic intoxication. A total of 75 patients (45 men and 30 women) aged 23 to 66 years (mean age, 53±2.1 years) with Stage VD CKF were examined. The levels of parathyroid hormone (PTH), calcium, phosphorus, the morphogenetic protein FGF-23, and the cardiospecific protein troponin I were investigated. Doppler echocardiography was performed on an Aloka 4000 machine. Left ventricular (LV) mass index (LVMI), LV systolic and diastolic function, and peak systolic blood flow velocity in the aortic arch (Vps) were estimated. As LVMI became higher, there were increases in the level of PTH and that of FGF-23 that plays a significant role in the processes of bone remodeling and vascular calcification. Analysis of correlations between a change in FGF-23 concentrations depending on the morphological and functional parameters of the cardiovascular system (CVS) revealed a strong direct correlation between FGF-23 levels and LVMI (r=0.746; p<0.01), a significant inverse correlation between FGF-23 and ejection fraction (r=-0.901; p<0.05), and a direct correlation of FGF-23 and troponin I (r=0.544; p<0.05). FGF-2 increasing from moderate to very high levels indicates that there is a high risk for remodeling processes in the CVS even in the absence of baseline echocardiographic signs of myocardial hypertrophy, normal aortic pulse wave velocity, and compensation of other risk factors, such as hypertension, uremia, hyperparathyroidism, even without increasing the markers of cardiovascular events, such as hyperphosphatemia. The elevated level of FGF-23 suggests that there is a need for cardioprotective therapy, the goal of which is to correct of the level of this factor.

The role of fibroblast growth factor 2 in patients with uterine smooth muscle tumors: an immunohistochemical study

ObjectiveFibroblast growth factor 2 (FGF-2) is considered to be a potent stimulator of angiogenesis and seems therefore to play an important role in the growth of tumors. We compared the immunohistochemical profile of FGF-2 in patients with uterine leiomyomas, smooth muscle tumors of uncertain malignant potential (STUMP) and leiomyosarcoma (LMS). Furthermore, we tried to clarify the prognostic role of FGF-2 in uterine leiomyosarcoma. Study designFGF-2 expression was investigated by immunohistochemistry from paraffin-embedded tissue in 26 patients with leiomyoma, in 24 cases with STUMP and in 21 patients with LMS. The immunohistochemical profile of these 3 tumor entities was compared and regarding LMS correlated with different clinicopathologic parameters. ResultsFGF-2 was expressed in 85% of leiomyomas, in 88% of STUMP and in 57% of LMS. Significant differences regarding the frequency of FGF-2 expression were observed between leiomyoma and LMS as well as between STUMP and LMS (p<0.05). In uterine LMS FGF-2 expression was statistically more frequent in cases with high histological grade (p<0.05). Furthermore, FGF-2 positive tumors demonstrated a statistically significant higher rate of recurrence disease and tumor progression (p=0.005). Disease free as well as overall survival was significantly shortened in patients with FGF-2 positive compared to FGF-2 negative tumors (p<0.05). ConclusionThe significant correlation between FGF-2 expression and high histological grade indicates that FGF-2 might work as a negative predictive factor. Higher rates of recurrence disease as well as shortened disease free and overall survival among FGF-2 positive LMS support the potential role as prognosticator for poor clinical outcome.

The mechanistic role of fibroblast growth factor 21 in growth hormone resistance secondary to chronic childhood conditions

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Impact of FGF23 level on calcium and phosphorus levels in post-renal transplantation.

Introduction: The level of fibroblast growth factor 23 (FGF23) may be considered as a prognostic factor for assessing renal function in regulating components of phosphate and vitamin D hemostasis. Objectives: The present study aimed to evaluate the prognostic value of FGF23 level to predict renal function after renal transplantation. Patients and Methods: Fifteen consecutive patients scheduled for renal transplantation. To assess renal function status, the MDRD formula and isotope scan were applied. The study endpoint was to assess the level of FGF23 and other factors involving calcium and phosphorus metabolism before and also 3 and 12 months after transplantation and also to determine role of FGF23 to predict postoperative renal function. Results: The mean level of FGF23 was 839.51±694.56 ρg/mL at baseline that reduced to 44.31±22.01 ρg/mL and 20.13±36.50 ρg/mL, 3 and 12 months after initial assessment. The levels of FGF23 was significantly lower at 3 and 12 months after baseline (P=0.01 and P=0.02, respectively) with no difference in FGF23 level between the time points of 3 and 12 months after transplantation. Baseline level of FGF23 was found to be higher in the patients with higher glomerular filtration rate (GFR), in older patients, in males, in those patients with diabetic nephropathy, in those with acceptable renal function than in patients who suffered transplant rejection. Conclusion: The level of postoperative FGF23 is an important marker for secretion of phosphorus from kidneys emphasizing the central role of FGF23 marker to regulate calcium and phosphorus metabolism after a successful renal transplantation.

P38 (Mapk14/11) occupies a regulatory node governing entry into primitive endoderm differentiation during preimplantation mouse embryo development.

During mouse preimplantation embryo development, the classically described second cell-fate decision involves the specification and segregation, in blastocyst inner cell mass (ICM), of primitive endoderm (PrE) from pluripotent epiblast (EPI). The active role of fibroblast growth factor (Fgf) signalling during PrE differentiation, particularly in the context of Erk1/2 pathway activation, is well described. However, we report that p38 family mitogen-activated protein kinases (namely p38α/Mapk14 and p38β/Mapk11; referred to as p38-Mapk14/11) also participate in PrE formation. Specifically, functional p38-Mapk14/11 are required, during early-blastocyst maturation, to assist uncommitted ICM cells, expressing both EPI and earlier PrE markers, to fully commit to PrE differentiation. Moreover, functional activation of p38-Mapk14/11 is, as reported for Erk1/2, under the control of Fgf-receptor signalling, plus active Tak1 kinase (involved in non-canonical bone morphogenetic protein (Bmp)-receptor-mediated PrE differentiation). However, we demonstrate that the critical window of p38-Mapk14/11 activation precedes the E3.75 timepoint (defined by the initiation of the classical ‘salt and pepper’ expression pattern of mutually exclusive EPI and PrE markers), whereas appropriate lineage maturation is still achievable when Erk1/2 activity (via Mek1/2 inhibition) is limited to a period after E3.75. We propose that active p38-Mapk14/11 act as enablers, and Erk1/2 as drivers, of PrE differentiation during ICM lineage specification and segregation.

Elevated fibroblast growth factor-23 and risk of cardiovascular disease or mortality in the general population: A meta-analysis

Elevated fibroblast growth factor-23 and risk of cardiovascular disease or mortality in the general population: A meta-analysis

Significantly higher peripheral fibroblast growth factor-2 levels in patients with major depressive disorder: A preliminary meta-analysis under MOOSE guidelines.

In vivo and in vitro studies demonstrate the important roles of fibroblast growth factor (FGF) and FGF receptors (FGFRs) in neural survival, neurogenesis, oxidative stress, and emotional behavior. However, evidence on the role of FGF and FGFR in the pathophysiology of major depressive disorder (MDD) remains limited and inconclusive. This preliminary meta-analysis aimed to examine changes in peripheral or central FGF and FGFR levels in patients with MDD. Electronic research through platform of PubMed and ClinicalTrials.gov. We used the inclusion criteria: articles discussing the comparisons of FGF levels, either in peripheral or central environment, in patients with MDD and in healthy controls (HC); articles on clinical trials in humans; and case-control trials. Case reports or series and nonclinical trials were excluded. Using a thorough literature search, the FGF/FGFR levels in patients with MDD and HC were compared. Four studies on peripheral FGF-2 and 3 on central FGF-2 and FGFR1 levels were included. The findings reveal significantly higher peripheral FGF-2 protein and central FGFR1 RNA levels in patients with MDD than in HC (P = 0.005 and 0.006, separately), but no significant association with clinical variables. There was also no significant difference in the central FGF-2 levels in patients with MDD and in HC (P = 0.180). The study has limitations of a small number of included studies, lack of meta-analysis of the FGF changes along with treatment, and lack of direct evidence on correlation of peripheral FGF-2 with central FGF-2 levels. This preliminary meta-analysis points out a new direction for future studies investigating the relationship among MDD, oxidative stress, and the FGF family.

FGF21 ameliorates nonalcoholic fatty liver disease by inducing autophagy.

The aim of this study is to evaluate the role of fibroblast growth factor 21 (FGF21) in nonalcoholic fatty liver disease (NAFLD) and seek to determine if its therapeutic effect is through induction of autophagy. In this research, Monosodium L-glutamate (MSG)-induced obese mice or normal lean mice were treated with vehicle, Fenofibrate, and recombinant murine FGF21, respectively. After 5weeks of treatment, metabolic parameters including body weight, blood glucose and lipid levels, hepatic and fat gene expression levels were monitored and analyzed. Also, fat-loaded HepG2 cells were treated with vehicle or recombinant murine FGF21. The expression levels of proteins associated with autophagy were detected by western blot, real-time PCR, and transmission electron microscopy (TEM). Autophagic flux was monitored by laser confocal microscopy and western blot. Results showed that FGF21 significantly reduced body weight (P<0.01) and serum triglyceride, improved insulin sensitivity, and reversed hepatic steatosis in the MSG model mice. In addition, FGF21 significantly increased the expression of several proteins related to autophagy both in MSG mice and fat-loaded HepG2 cells, such as microtubule associated protein 1 light chain 3, Bcl-2-interacting myosin-like coiled-coil protein-1 (Beclin-1), and autophagy-related gene 5. Furthermore, the evidence of TEM revealed an increased number of autophagosomes and lysosomes in the model cells treated with FGF21. In vitro experimental results also showed that FGF21 remarkably increased autophagic flux. Taken together, FGF21 corrects multiple metabolic parameters on NAFLD in vitro and in vivo by inducing autophagy.

Abstract 4083: Tumor associated macrophages mediates the oncogenic effect of FGF18 in ovarian cancer

Abstract Epithelial ovarian cancer is the fifth leading cause of cancer-related death among women and has the highest case-fatality rate among gynecologic cancers. Effective management of this deadly disease still remains scanty due to the inadequate understanding of the molecular mechanisms associated with the tumor progression and prognosis. We have previously reported the tumor-promoting role of Fibroblast growth factor 18 (FGF18), which have been identified through genomic analysis of ovarian tumors. Initial studies suggested FGF18 promotes ovarian tumor progression through NF-κB pathway mediated elevation of proinflammatory cytokines, which mediate the increased tumor burden, angiogenesis and infiltration of macrophages in FGF18 expressing xenografts. Based on these findings, the present study aims to delineate the mechanism by which FGF18 modulates the phenotype of tumor associated macrophages (TAMs) as well as the reciprocal tumor-promoting feedback from the TAMs which potentially contributes FGF18 mediated ovarian tumorigenesis. Immunohistochemical staining of a tissue array comprising 216 archived high-grade advanced stage serous ovarian tumor specimens revealed a significant correlation between the FGF18 expression and infiltration of M2-polarized macrophages (by CD163). In addition, the density of intratumoral M2 TAMs inversely associated with patients’ overall survival as a negative prognostic factor independent to age, tumor grade and debulking status. These findings suggest intratumoral TAMs may play an important role in ovarian tumorigenesis. In vitro co-culture studies further demonstrated that human monocyte cell line THP-1 or murine peritoneal macrophage cell line IC-21 could significantly activate the NF-κB pathway and increase the production of various proinflammatory cytokines in A224 ovarian cancer cells. Co-culture also increased the migratory potential of A224 cells. Addition of an IKKβ inhibitor into the co-culture system nullified the cytokine production and migration of tumor cells promoted by monocytes/macrophages, implicating the involvement of canonical NF-κB signaling in the crosstalk. Conversely, liposome clodronate mediated in vivo macrophage depletion significantly shrunk the tumor burden of the intraperitoneal xenograft derived from FGF18 overexpressing SKOV3 cells, while minimal effect was observed over the control RFP overexpressing xenograft. Besides, macrophage depletion also markedly decreased the intratumoral microvessel density induced by FGF18 overexpression. Taken together, our data potentially suggest TAMs may mediate the FGF18 related ovarian tumorigenesis by augmenting the proinflammatory status of the tumors. Citation Format: Wei Wei, Michael Birrer. Tumor associated macrophages mediates the oncogenic effect of FGF18 in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4083.

FGFs: crucial factors that regulate tumour initiation and progression

Fibroblast growth factors (FGFs) are crucial signalling molecules involved in normal cell growth, differentiation and proliferation. Over the past few decades, a large body of research has illustrated effects of individual FGFs on tumour initiation and progression. Tumour development is commonly accompanied with generation of new blood and lymph vessels, which support enhanced cell proliferation. Moreover, acquisition of tumour cells of the epithelial-mesenchymal transition (EMT) phenotype, enhances tumour cell migration and invasion potentials, crucial steps in tumour metastasis. This review summarizes recent findings concerning roles of FGFs in angiogenesis, lymphangiogenesis and EMT.

The role of fibroblast growth factor 23 and Klotho in uremic cardiomyopathy.

In chronic kidney disease (CKD), multiple factors contribute to the development of cardiac hypertrophy by directly targeting the heart or indirectly by inducing systemic changes such as hypertension, anemia, and inflammation. Furthermore, disturbances in phosphate metabolism have been identified as nonclassical risk factors for cardiovascular mortality in these patients. With declining kidney function, the physiologic regulators of phosphate homeostasis undergo changes in their activity as well as their circulating levels, thus potentially contributing to cardiac hypertrophy once they are out of balance. Recently, two of these phosphate regulators, fibroblast growth factor 23 (FGF23) and Klotho, have been shown to affect cardiac remodeling, thereby unveiling a novel pathomechanism of cardiac hypertrophy in CKD. Here we discuss the potential direct versus indirect effects of FGF23 and the soluble form of Klotho on the heart, and their crosstalk in the regulation of cardiac hypertrophy. In models of CKD, FGF23 can directly target cardiac myocytes via FGF receptor 4 and induce cardiac hypertrophy in a blood pressure-independent manner. Soluble Klotho may directly target the heart via an unknown receptor thereby protecting the myocardium from pathologic stress stimuli that are associated with CKD, such as uremic toxins or FGF23. Elevated serum levels of FGF23 and reduced serum levels of soluble Klotho contribute to uremic cardiomyopathy in a synergistic manner.

Multiple faces of fibroblast growth factor-23.

This review examines the role of fibroblast growth factor-23 (FGF-23) in mineral metabolism, innate immunity and adverse cardiovascular outcomes. FGF-23, produced by osteocytes in bone, activates FGFR/α-Klotho (α-Kl) 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-Kl in activated macrophages, creating a proinflammatory paracrine signaling pathway that counters the antiinflammatory actions of vitamin D. FGF-23 also inhibits angiotensin-converting enzyme 2 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-Kl. Although secreted forms of α-Kl have FGF-23 independent effects, the possibility of α-Kl independent effects of FGF-23 is controversial and requires additional experimental validation. 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.

Region-specific effects of developmental exposure to cocaine on fibroblast growth factor-2 expression in the rat brain.

Adolescence is a period of high vulnerability to drugs of abuse and alterations of the proper developmental trajectory via psychostimulant exposure might change the physiological brain homeostasis. By microdissection of brain areas via punching, we investigated whether repeated exposure to cocaine during adolescence (from postnatal day 28 [PND28] to PND42) has altered fibroblast growth factor-2 (FGF-2) messenger RNA (mRNA) levels in selected brain subregions critical for the action of cocaine. We found a reduction of FGF-2 mRNA levels in ventral tegmental area (VTA), where mesocortical and mesolimbic pathways originate. The analysis of the trophic factor levels in the distal projecting regions revealed a selective reduction of FGF-2 mRNA levels in infralimbic (IL) subregion of the medial prefrontal cortex (the terminal region of the mesocortical pathway) and in the nucleus accumbens core (cNAc) (the terminal region of the mesolimbic pathway). Last, we found reduced FGF-2 mRNA levels also in brain regions which, although in a different manner, contribute to the reward system, i.e., the central nucleus of amygdala (cAmy) and the ventral portion of hippocampus (vHip). The widespread and coordinated reduction of FGF-2 mRNA levels across the brain's reward neurocircuitry might represent a defensive strategy set in motion to oppose to the psychostimulant properties of cocaine. Moreover, given the role of FGF-2 in modulating mood disorders, the reduced trophic support here observed might sustain the negative emotional state set in motion by repeated exposure to cocaine.

Alveologenesis: key cellular players and fibroblast growth factor 10 signaling.

BackgroundAlveologenesis is the last stage in lung development and is essential for building the gas-exchanging units called alveoli. Despite intensive lung research, the intricate crosstalk between mesenchymal and epithelial cell lineages during alveologenesis is poorly understood. This crosstalk contributes to the formation of the secondary septae, which are key structures of healthy alveoli.ConclusionsA better understanding of the cellular and molecular processes underlying the formation of the secondary septae is critical for the development of new therapies to protect or regenerate the alveoli. This review summarizes briefly the alveologenesis process in mouse and human. Further, it discusses the current knowledge on the epithelial and mesenchymal progenitor cells during early lung development giving rise to the key cellular players (e.g., alveolar epithelial cell type I, alveolar epithelial cell type II, alveolar myofibroblast, lipofibroblast) involved in alveologenesis. This review focusses mainly on the role of fibroblast growth factor 10 (FGF10), one of the most important signaling molecules during lung development, in epithelial and mesenchymal cell lineage formation.

The role of fibroblast growth factor in the destruction in rheumatoid arthritis

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)