Fibroblast Growth Factor Family Research Articles

The Interactions of Nintedanib and Oral Anticoagulants-Molecular Mechanisms and Clinical Implications.

Nintedanib is a synthetic orally active tyrosine kinase inhibitor, whose main action is to inhibit the receptors of the platelet-derived growth factor, fibroblast growth factor and vascular endothelial growth factor families. The drug also affects other kinases, including Src, Flt-3, LCK, LYN. Nintedanib is used in the treatment of idiopathic pulmonary fibrosis, chronic fibrosing interstitial lung diseases and lung cancer. The mechanism of action suggests that nintedanib should be considered one of the potential agents for inhibiting and revising the fibrosis process related to COVID-19 infections. Due to the known induction of coagulation pathways during COVID-19 infections, possible interaction between nintedanib and anticoagulant seems to be an extremely important issue. In theory, nintedanib could increase the bleeding risk, thrombosis and lead to thrombocytopenia. The data from clinical trials on the concomitant use of nintedanib and antithrombotic agents is very limited as this patient group was within the standard exclusion criteria. Nintedanib is an important therapeutic option, despite its interaction with anticoagulants. If anticoagulant therapy is necessary, the more effective and safer option is the concomitant administration of DOACs and nintedanib, especially when drug-monitored therapy will be used in patients at high risk of bleeding complications.

Targeting Drugs Against Fibroblast Growth Factor(s)-Induced Cell Signaling.

The fibroblast growth factor (FGF) family is comprised of 23 highly regulated monomeric proteins that regulate a plethora of developmental and pathophysiological processes, including tissue repair, wound healing, angiogenesis, and embryonic development. Binding of FGF to fibroblast growth factor receptor (FGFR), a tyrosine kinase receptor, is facilitated by a glycosaminoglycan, heparin. Activated FGFRs phosphorylate the tyrosine kinase residues that mediate induction of downstream signaling pathways, such as RAS-MAPK, PI3K-AKT, PLCγ, and STAT. Dysregulation of the FGF/FGFR signaling occurs frequently in cancer due to gene amplification, FGF activating mutations, chromosomal rearrangements, integration, and oncogenic fusions. Aberrant FGFR signaling also affects organogenesis, embryonic development, tissue homeostasis, and has been associated with cell proliferation, angiogenesis, cancer, and other pathophysiological changes. This comprehensive review will discuss the biology, chemistry, and functions of FGFs, and its current applications toward wound healing, diabetes, repair and regeneration of tissues, and fatty liver diseases. In addition, specific aberrations in FGFR signaling and drugs that target FGFR and aid in mitigating various disorders, such as cancer, are also discussed in detail. Inhibitors of FGFR signaling are promising drugs in the treatment of several types of cancers. The clinical benefits of FGF/FGFR targeting therapies are impeded due to the activation of other RTK signaling mechanisms or due to the mutations that abolish the drug inhibitory activity on FGFR. Thus, the development of drugs with a different mechanism of action for FGF/FGFR targeting therapies is the recent focus of several preclinical and clinical studies.

FGF Expression in HPV16-positive and -negative SCC After Treatment With Small-molecule Tyrosine Kinase Inhibitors and Everolimus

Targeted therapies in the treatment of head and neck squamous cell carcinoma (HNSCC) are subject to extensive research. Different mutations of genes belonging to the fibroblast growth factor (FGF) family have been detected in HNSCC. In this study, we examined the expression of FGF1 and FGF2 after treatment with small-molecule tyrosine kinase inhibitors (TKIs) and an inhibitor of mechanistic target of rapamycin (mTOR) in vitro using human papillomavirus (HPV)-positive and -negative SCC lines. Cells of two human HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with 20 μmol/l of erlotinib, gefitinib, nilotinib, dasatinib, or everolimus for 24-96 h. Cell proliferation was assessed by proliferation assay and the protein concentrations of FGF1 and FGF2 by sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those for untreated HPV-negative SCC cells. FGF1 and FGF2 were detected in all three tested cell lines. The tested TKIs significantly (p<0.05 reduced) FGF1 expression in the UMSCC-11A cell line within the first 24 h. At later time points, the tested TKIs and everolimus significantly (p<0.05) increased FGF1 and FGF2 expression in HPV-negative and -positive cancer cell lines. The effect was stronger in the HPV-positive cell line. Alterations in FGF signalling are considered to be relevant drivers of tumourigenesis in some HNSCCs. Our results show that the expression of FGF1 and -2 can be influenced effectively by small-molecule TKIs and everolimus. Based on our data, future research should include combinations of specific FGF inhibitors, mTOR inhibitors and other TKIs in the treatment of HNSCC and research on FGF-mediated drug escape mechanisms.

Klotho, Aging, and the Failing Kidney.

Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of aging.

Abstract 2976: Targeting fibroblast growth factor (FGF) signals induced type I IFN regulated response and Immunogenic cell death (ICD) markers in tumor cells with activated FGF signals

Abstract Introduction: The FGF family plays key roles in many developmental and physiological processes. Aberrant activation of FGF signals (receptor mutations, fusions, and amplifications of ligands or receptors) have been reported, and considered to cause malignant cancers. Targeting FGFR suppresses proliferation and survival of tumor cells with activated FGF signal. However, the role of tumor FGFR inhibition in tumor microenvironments (TMEs) is largely still unknown. Lenvatinib (LEN) is a multi-targeted tyrosine kinase inhibitor that mainly inhibits VEGFR1-3 and FGFR1-4. Previously we showed that LEN inhibited tumor FGF signal, and induced cancer cell death, which had a role in antitumor activity. Here, we investigated roles of targeting tumor FGFR in TMEs using LEN or FGFR1-3 specific inhibitor E7090 in tumor cells with activated FGF signals. Methods: To examine effects of FGF signal on gene expression profile (GEP) of tumor cells, mouse breast tumor 4T1 cell lines expressing Luc2 and AcGFP (4T1-Luc), human hepatocellular carcinoma (HCC) Hep3B2.1-7 and HuH-7 cells with FGF19 overexpression, and an endometrial cancer (EC) AN3CA cell line harboring FGFR2 mutation were treated with LEN or E7090. GEP was analyzed by RNA-Seq or qPCR in the 4T1-Luc model. Pathway enrichment analysis using RNA-Seq data was conducted by Ingenuity pathway analysis (IPA). Expression levels of type I IFN-related genes were analyzed in HCC and EC cell lines. Expressions of Cxcl10 and HMGB1 in culture supernatant were measured by ELISA. Cell surface expressions of PD-L1, MHC class I molecules and Calreticulin (CRT) were determined by flow cytometry. Results: Unbiased pathway analysis using RNA-Seq data (fold change &amp;gt;2 or &amp;lt;0.5, TPM in NT-average &amp;gt;1) from 4T1-Luc cells treated with LEN or E7090 identified Interferon (IFN) signal as one of the top 3 most significantly regulated pathways with several genes known to regulate tumor immunity. qPCR analysis showed that LEN and E7090 increased expression of type I IFN-related genes in human HCC and EC cell lines. LEN significantly increased CXCL10 in culture supernatant and expression of MHC class I and PD-L1 on cell surfaces of 4T1-Luc and Hep3B2.1-7 cells. E7090 also increased Cxcl10 in culture sup and expressions of MHC class I and PD-L1 on cell surface of 4T1-Luc cells. In addition to type I IFN-response, we found that LEN and E7090 might regulate ICD evidenced by increased expression levels of cell surface CRT, and Len increased secreted HMGB1 in culture sup of Hep3B2.1-7 cells. Conclusion: Our results suggested that tumor FGF signals modulated immune response in TMEs through regulating interferon signal. Tumor FGF signal inhibition by LEN and E7090 may enhance antitumor immune response in the TMEs of that were immune suppressive with activated FGF signals. Further analyses will be warranted. Citation Format: Taisuke Hoshi, Yu Kato, Yasuhiro Funahashi. Targeting fibroblast growth factor (FGF) signals induced type I IFN regulated response and Immunogenic cell death (ICD) markers in tumor cells with activated FGF signals [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2976.

FGF5 Regulates Schwann Cell Migration and Adhesion.

The fibroblast growth factor (FGF) family polypeptides play key roles in promoting tissue regeneration and repair. FGF5 is strongly up-regulated in Schwann cells of the peripheral nervous system following injury; however, a role for FGF5 in peripheral nerve regeneration has not been shown up to now. In this report, we examined the expression of FGF5 and its receptors FGFR1-4 in Schwann cells of the mouse sciatic nerve following injury, and then measured the effects of FGF5 treatment upon cultured primary rat Schwann cells. By microarray and mRNA sequencing data analysis, RT-PCR, qPCR, western blotting and immunostaining, we show that FGF5 is highly up-regulated in Schwann cells of the mouse distal sciatic nerve following injury, and FGFR1 and FGFR2 are highly expressed in Schwann cells of the peripheral nerve both before and following injury. Using cultured primary rat Schwann cells, we show that FGF5 inhibits ERK1/2 MAP kinase activity but promotes rapid Schwann cell migration and adhesion via the upregulation of N-cadherin. Thus, FGF5 is an autocrine regulator of Schwann cells to regulate Schwann cell migration and adhesion.

Quantitative gene expression dynamics of key placode signalling factors in the embryonic chicken scleral ossicle system

Development of the scleral ossicles, a ring of bony elements within the sclera, is directed by a series of papillae that arise from placodes in the conjunctival epithelium over a 1.5-day induction period in the chicken embryo. The regular spacing of the papillae around the corneal-scleral limbus suggests that their induction may be regulated by a reaction-diffusion mechanism, similar to other epithelial appendages. Some key placode signalling molecules, including β-catenin, are known to be expressed throughout the induction period. However, others have been studied only at certain stages or have not been successfully detected. Here we use qPCR to study the gene expression patterns of the wingless integration (WNT)/β-catenin, bone morphogenetic protein (BMP), ectodysplasin (EDA), fibroblast growth factor (FGF) and hedgehog (HH) signalling families in discrete regions of the eye throughout the complete conjunctival placode and papillae induction period. This comprehensive analysis revealed a variable level of gene expression within specific eye regions, with some genes exhibiting high, moderate or low changes. Most genes exhibited an initial increase in gene expression, followed by a decrease or plateau as development proceeded, suggesting that some genes are important for a brief initial period whilst the sustained elevated expression level of other genes is needed for developmental progression. The timing or magnitude of these changes, and/or the overall gene expression trend differed in the temporal, nasal and/or dorsal eye regions for some, but not all genes, demonstrating that gene expression may vary across different eye regions. Temporal and nasal EDA receptor (EDAR) had the greatest number of strong correlations (r > 0.700) with other genes and β-catenin had the greatest number of moderate correlations (r = 0.400–0.700), while EDA had the greatest range in correlation strengths. Among the strongly correlated genes, two distinct signalling modules were identified, connected by some intermediate genes. The dynamic gene expression patterns of the five signalling pathways studied here from conjunctival placode formation through to papillae development is consistent with other epithelial appendages and confirms the presence of a conserved induction and patterning signalling network. Two unique gene expression patterns and corresponding gene interaction modules suggest functionally distinct roles throughout placode development. Furthermore, spatial differences in gene expression patterns among the temporal, nasal and dorsal regions of the eye may indicate that the expression of certain genes is influenced by mechanical forces exerted throughout development. Therefore, this study identifies key placode signalling factors and their interactions, as well as some potential region-specific features of gene expression in the scleral ossicle system and provides a basis for further exploration of the spatial expression of these genes and the patterning mechanism(s) active throughout conjunctival placode and papillae formation.

Genome-wide estrogen receptor-α binding and action in human endometrial stromal cells

To investigate the gene targets of estradiol (E2)-estrogen receptor-α (ESR1) in human endometrial stromal cells. Basic science. University research center. Premenopausal women with or without endometriosis. Primary cultures of human endometrial stromal cells from healthy endometrium, with or without small-interfering RNA (siRNA) knockdown of ESR1 expression, were treated with E2 or vehicle control. Genome-wide RNA expression by RNA sequencing was compared in endometrial stromal cells with or without siRNA knockdown of ESR1 in the presence or absence of E2. Genome-wide recruitment of ESR1 to chromatin was assessed by chromatin immunoprecipitation sequencing. Gene expression by real-time qualitative polymerase chain reaction of a potential E2-ESR1 target gene was determined in endometrial stromal cells and endometriotic stromal cells. We identified several important pathways that are dependent on E2-ESR1 signaling in endometrial stromal cells, including progesterone signaling, cell-matrix adhesion, and cytoskeleton rearrangement, as well as paracrine signaling by members of the fibroblast growth factor family. We detected a total of 709 ESR1 target sites on chromatin. By integrating data on genome-wide transcriptomic changes and E2-ESR1 binding sites, we identified inositol polyphosphate phosphatase type II (INPP4B) as a candidate E2-mediated suppressor of proliferation in healthy endometrial cells. INPP4B was downregulated in endometriosis-derived stromal cells. E2-ESR1 activates genes involved in human endometrial stromal cell cycle regulation, progesterone response, and production of stromal growth factors. Understanding the direct role of estrogen on the endometrial stroma and identifying downstream targets of E2-ESR1 can inform the development of targeted therapies for endometriosis and diminished endometrial receptivity.

The FGF/FGFR system in the physiopathology of the prostate gland.

Fibroblast growth factors (FGFs) are a family of proteins possessing paracrine, autocrine, or endocrine functions in a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis, wound repair, and cancer. Canonical FGFs bind and activate tyrosine kinase FGF receptors (FGFRs), triggering intracellular signaling cascades that mediate their biological activity. Experimental evidence indicates that FGFs play a complex role in the physiopathology of the prostate gland that ranges from essential functions during embryonic development to modulation of neoplastic transformation. The use of ligand- and receptor-deleted mouse models has highlighted the requirement for FGF signaling in the normal development of the prostate gland. In adult prostate, the maintenance of a functional FGF/FGFR signaling axis is critical for organ homeostasis and function, as its disruption leads to prostate hyperplasia and may contribute to cancer progression and metastatic dissemination. Dissection of the molecular landscape modulated by the FGF family will facilitate ongoing translational efforts directed toward prostate cancer therapy.

Fibroblast Growth Factor-14 Acts as Tumor Suppressor in Lung Adenocarcinomas.

Investigation of the molecular dynamics in lung cancer is crucial for the development of new treatment strategies. Fibroblast growth factor (FGF) 14 belongs to the FGF family, which might play a crucial role in cancer progression. We analyzed lung adenocarcinoma (LUAC) patients samples and found that FGF14 was downregulated, correlating with reduced survival and oncogenic mutation status. FGF14 overexpression in lung cancer cell lines resulted in decreased proliferation, colony formation, and migration, as well as increased expression of epithelial markers and a decreased expression of mesenchymal markers, indicating a mesenchymal to epithelial transition in vitro. We verified these findings using small interfering RNA against FGF14 and further confirmed the suppressive effect of FGF14 in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ immunodeficient xenograft tumor model. Moreover, FGF14 overexpressing tumor cell RNA sequencing data suggests that genes affected by FGF14 were related to the extracellular matrix, playing a role in proliferation and migration. Notably, newly identified FGF14 target genes, adenosine deaminase RNA specific B1 (ADARB1), collagen and calcium-binding epidermal growth factor domain-containing protein 1 (CCBE1), α1 chain of collagen XI (COL11A1), and mucin 16 (MUC16) expression was negatively correlated with overall survival when FGF14 was downregulated in LUAC. These findings led us to suggest that FGF14 regulates proliferation and migration in LUAC.

Fibroblast Growth Factor: Promising Target for Schizophrenia.

Schizophrenia is one of the most debilitating mental disorders around the world. It is characterized by neuroanatomical or biochemical changes. The role of the fibroblast growth factors (FGFs) system in schizophrenia has received considerable attention in recent years. Various changes in the gene expression and/or level of FGFs have been implicated in the etiology, symptoms and progression of schizophrenia. For example, studies have substantiated an interaction between FGFs and the signaling pathway of dopamine receptors. To understand the role of this system in schizophrenia, the databases of Open Access Journals, Web of Science, PubMed (NLM), LISTA (EBSCO), and Google Scholar with keywords including fibroblast growth factors, dopamine, schizophrenia, psychosis, along with neurotrophic were searched. In conclusion, the FGF family represent molecular candidates as new drug targets and treatment targets for schizophrenia.

Fibroblast Growth Factors in the Management of Acute Kidney Injury Following Ischemia-Reperfusion.

Ischemia-reperfusion injury (IRI), which is triggered by a transient reduction or cessation of blood flow followed by reperfusion, is a significant cause of acute kidney injury (AKI). IRI can lead to acute cell death, tissue injury, and even permanent organ dysfunction. In the clinic, IRI contributes to a higher morbidity and mortality and is associated with an unfavorable prognosis in AKI patients. Unfortunately, effective clinical drugs to protect patients against the imminent risk of renal IRI or treat already existing AKI are still lacking. Fibroblast growth factors (FGFs) are important regulators of key biological and pathological processes, such as embryonic development, metabolic homeostasis and tumorigenesis through the regulation of cell differentiation, migration, proliferation and survival. Accumulating evidence suggests that altered expression of endogenous FGFs is associated with IRI and could be instrumental in mediating the repair process. Therefore, FGFs have been proposed as potential biomarkers in the clinic. More importantly, exogenous FGF ligands have been reported to protect against renal IRI and display promising features for therapy. In this review, we summarize the evidence and mechanisms of AKI following IRI with a focus on the therapeutic capacity of several members of the FGF family to treat AKI after IRI.

Satellite cells and their regulation in livestock.

Satellite cells are the myogenic stem and progenitor population found in skeletal muscle. These cells typically reside in a quiescent state until called upon to support repair, regeneration, or muscle growth. The activities of satellite cells are orchestrated by systemic hormones, autocrine and paracrine growth factors, and the composition of the basal lamina of the muscle fiber. Several key intracellular signaling events are initiated in response to changes in the local environment causing exit from quiescence, proliferation, and differentiation. Signals emanating from Notch, wingless-type mouse mammary tumor virus integration site family members, and transforming growth factor-β proteins mediate the reversible exit from growth 0 phase while those initiated by members of the fibroblast growth factor and insulin-like growth factor families direct proliferation and differentiation. Many of these pathways impinge upon the myogenic regulatory factors (MRF), myogenic factor 5, myogenic differentiation factor D, myogenin and MRF4, and the lineage determinate, Paired box 7, to alter transcription and subsequent satellite cell decisions. In the recent past, insight into mouse transgenic models has led to a firm understanding of regulatory events that control satellite cell metabolism and myogenesis. Many of these niche-regulated functions offer subtle differences from their counterparts in livestock pointing to the existence of species-specific controls. The purpose of this review is to examine the mechanisms that mediate large animal satellite cell activity and their relationship to those present in rodents.

FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway.

Major depressive disorder is a serious neuropsychiatric disorder with high rates of recurrence and mortality. Many studies have supported that inflammatory processes play a central role in the etiology of depression. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factors (FGFs) family, regulates a variety of pharmacological activities, including energy metabolism, glucose and lipid metabolism, and insulin sensitivity. In addition, recent studies showed that the administration of FGF21, a regulator of metabolic function, had therapeutic effects on mood stabilizers, indicating that FGF21 could be a common regulator of the mood response. However, few studies have highlighted the antidepressant effects of FGF21 on lipopolysaccharide (LPS)-induced mice, and the anti-inflammatory mechanism of FGF21 in depression has not yet been elucidated. The purpose of the current study was to determine the antidepressant effects of recombinant human FGF21 (rhFGF21). The effects of rhFGF21 on depression-like behaviors and the inflammatory signaling pathway were investigated in both an LPS-induced mouse model and primary microglia in vitro. The current study demonstrated that LPS induced depressive-like behaviors, upregulated proinflammatory cytokines, and activated microglia in the mouse hippocampus and activated the inflammatory response in primary microglia, while pretreatment with rhFGF21 markedly improved depression-like behavior deficits, as shown by an increase in the total distance traveled and number of standing numbers in the open field test (OFT) and a decrease in the duration of immobility in the tail suspension test (TST) and forced swimming test (FST). Furthermore, rhFGF21 obviously suppressed expression levels of the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) and inhibited microglial activation and the nuclear factor-κB (NF-κB) signing pathway. Moreover, coadministration of rhFGF21 with the fibroblast growth factor receptor 1 (FGFR1) inhibitor PD173074 significantly reversed these protective effects, indicating that the antidepressant effects of rhFGF21 occur through FGFR1 activation. Taken together, the results of the current study demonstrated for the first time that exogenous rhFGF21 ameliorated LPS-induced depressive-like behavior by inhibiting microglial expression of proinflammatory cytokines through NF-κB suppression. This new discovery suggests rhFGF21 as a new therapeutic candidate for depression treatment.

Progress in Research on the Role of FGF in the Formation and Treatment of Corneal Neovascularization.

Corneal neovascularization (CNV) is a sight-threatening disease usually associated with inflammatory, infectious, degenerative, and traumatic disorders of the ocular surface. Fibroblast growth factor (FGF) family members play an important role in angiogenesis to induce corneal neovascularization, which significantly affects the differentiation, proliferation, metastasis, and chemotaxis of vascular endothelial cells. Both acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) demonstrate positive staining in capillaries and induce corneal stromal cells. The anabolism of endothelial cells is induced by bFGF in corneal neovascularization. FGFs exert their effects via specific binding to cell surface-expressed specific receptors. We believe that both anti-FGF antibodies and anti-FGF receptor antibodies represent new directions for the treatment of CNV. Similar to anti-vascular endothelial growth factor antibodies, subconjunctival injection and eye drops can be considered effective forms of drug delivery.

FGF Signaling Pathway: A Key Regulator of Stem Cell Pluripotency.

Pluripotent stem cells (PSCs) isolated in vitro from embryonic stem cells (ESCs), induced PSC (iPSC) and also post-implantation epiblast-derived stem cells (EpiSCs) are known for their two unique characteristics: the ability to give rise to all somatic lineages and the self-renewal capacity. Numerous intrinsic signaling pathways contribute to the maintenance of the pluripotency state of stem cells by tightly controlling key transcriptional regulators of stemness including sex determining region Y box 2 (Sox-2), octamer-binding transcription factor (Oct)3/4, krueppel-like factor 4 (Klf-4), Nanog, and c-Myc. Signaling by fibroblast growth factor (FGF) is of critical importance in regulating stem cells pluripotency. The FGF family is comprised of 22 ligands that interact with four FGF receptors (FGFRs). FGF/FGFR signaling governs fundamental cellular processes such as cell survival, proliferation, migration, differentiation, embryonic development, organogenesis, tissue repair/regeneration, and metabolism. FGF signaling is mediated by the activation of RAS – mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT, Phospholipase C Gamma (PLCγ), and signal transducers and activators of transcription (STAT), which intersects and synergizes with other signaling pathways such as Wnt, retinoic acid (RA) and transforming growth factor (TGF)-β signaling. In the current review, we summarize the role of FGF signaling in the maintenance of pluripotency state of stem cells through regulation of key transcriptional factors.

Serum Endocrine Fibroblast Growth Factors as Potential Biomarkers for Chronic Kidney Disease and Various Metabolic Dysfunctions in Aged Patients.

Objective To prolong the health expectancy, it is important to prevent age-related diseases, such as osteoporosis and cerebrovascular disease, which are major causes of a bedridden state. Early predictable biomarkers for these diseases are urgently required in the clinical setting. Three members of the fibroblast growth factor (FGF) family - FGF19, FGF21, and FGF23 - are designated as endocrine FGFs and play crucial roles in various metabolic processes. We tried to clarify the clinical utility of endocrine FGFs as biomarkers for age-related diseases in elderly patients. Methods We examined the serum endocrine FGF levels and analyzed their association with various clinical parameters in 73 outpatients >60 years old as a single-center cross-sectional study. Results In a multivariable linear regression analysis, FGF19 was associated with ALT, a history of cardiovascular disease, and medication with active vitamin D3. FGF21 was associated with the estimated glomerular filtration rate (eGFR), triglyceride level, and hypertension. FGF23 was associated with the eGFR and the serum levels of 1,25-dihydroxy vitamin D3 and TRACP5b. In addition, a receiver operating characteristics analysis revealed that the measurement of FGF21 and FGF23 was useful for detecting chronic kidney disease (CKD) and its complications, including cardiovascular disease and metabolic bone disorder. Conclusion The measurement of FGF21 and FGF23 may be useful for evaluating CKD and its complications. Using serum endocrine FGFs as biomarkers for age-related conditions may help prevent elderly patients from entering a bedridden state.

Molecular description of fibroblast growth factor and mechanisms by which fibroblast growth factor-21 mediating biological actions and acting as a biologic biomarker of cardiovascular diseases

Fibroblast growth factor (FGF) family members are mostly secreted as signaling proteins with diverse functions in development and metabolism. FGFs can be classified as intracellular, paracrine, and endocrine FGFs by their action mechanisms. FGF-21 is a novel member of endocrine FGF subfamily with pleotropic actions. Recent findings indicate that FGF-21 can act as a cardiomyokine; that is, it is produced by cardiac cells and acts in an autocrine manner on the heart itself. The heart is sensitive to the effects of FGF-21, both systemic and locally generated, owing to the expression in cardiomyocytes of β-Klotho, the key coreceptor known to confer specific responsiveness to FGF-21 action. It has been shown to exert cardioprotective effects in against cardiac hypertrophy, myocardial infarction, cardiac inflammation, cardiac ischemia-reperfusion injury, diabetic cardiomyopathy, and oxidative stress. It also promotes energy supply to the heart through fatty acid β-oxidation. Intracellular mechanisms involving peroxisome proliferator-activated receptor α and sirtunin 1 mediate transcriptional regulation of the FGF-21 gene in response to exogenous stimuli. This review explores the molecular mechanism by which FGF-21 provides cardioprotection.

Expression and functional role of fibroblast growth factors (FGF) in placenta during different stages of pregnancy in water buffalo (Bubalus bubalis)

The present study documented the expression and functional role of Fibroblast growth factors (FGFs) family and their receptors (Fibroblast growth factor receptor, FGFRs) in placenta (Cotyledon; COT, Caruncle; CAR) during different stages of pregnancy in water buffalo. Samples were collected from Early pregnancy 1 (EP1); Early pregnancy 2 (EP2); Mid pregnancy (MP) and Late pregnancy (LP) while diestrus stage of oestrus cycle (NP) was taken as control. In addition, modulatory role of FGF2 on mRNA expression of von Willebrand factor (vWF), Proliferating cell nuclear antigen (PCNA), steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), 3β-hydroxysteroid dehydrogenase (3βHSD) and BCL2 Associated X (BAX) were studied in cultured trophoblast cells (TCC), obtained from EP2. Real-time PCR (qPCR), Western blot, and immunohistochemistry were applied to investigate mRNA and protein expressions, and the localization of examined factors whereas, P4 secretion was assessed by RIA. The mRNA and protein expression of FGFs and its receptors were maximum (P < 0.05) during EP (EP1 and EP2) in COT. However, FGFR1 and FGFR4 were upregulated (P < 0.05) during EP2 and MP in COT. Similarly, the mRNA and protein expression of FGFs and its receptors were upregulated (P < 0.05) during all stages of pregnancy in CAR. FGF family members were localized in the cytoplasm of trophoblast cells as well as in fetal blood vessels. At 100 ng/ml dosage, FGF2 stimulated the transcript of vWF maximally (P < 0.05). P4 secretion in trophoblast cells treated with FGF2 was maximum with the highest dose at 72 h. These findings corroborate that FGF acts locally in the trophoblast cells to modulate steroid hormone viz. progesterone synthesis, promote angiogenesis and favors cell survivability indicating that this factor may play an essential role in the regulation of placental formation and function in buffalo.

FGF9 knockout in GABAergic neurons induces apoptosis and inflammation via the Fas/caspase-3 pathway in the cerebellum of mice

Fibroblast growth factor 9 (FGF9) is a member of the fibroblast growth factor family and is widely expressed in the central nervous system (CNS). However, it is not clear how the working mechanism of FGF9 is involved in cerebellar development. To address this question, we deleted the Fgf9 gene specifically in GABAergic neurons or glutamatergic neurons, and demonstrated that Fgf9 ablation in GABAergic neurons rather than the glutamatergic neurons caused severe ataxia. We showed that FGF9 played a key role in the survival and development of Purkinje cells. GABAergic neuron-specific knockout of FGF9 (Fgf9VGAT) significantly affected the survival and development of Purkinje cells, disrupting Bergmann fiber scaffold formation and granule neuron migration in mice. RNA sequencing revealed that 976 differentially expressed genes (DEGs) were identified between Fgf9VGAT and control mice. The DEGs with significantly upregulated expression were found to be involved in apoptotic and inflammatory signaling. Selected genes including Fas, Bid, Mapk11, Cxcl10, CCl2, Bik and Fos, were validated by qRT-PCR and exhibited increases in expression in Fgf9VGAT mice compared to control mice similar to those seen in the RNA-sequencing data. The expression levels of apoptosis- and inflammation-related proteins were also increased, especially those of Fas and caspase-3 pathway related proteins. Interestingly, activated ERK signaling has been observed in apoptosis and inflammatory responses induced by deleting Fgf9 in GABAergic neurons.