Fibroblast Growth Factor Superfamily Research Articles

Fibroblast growth factor-21 alleviates proteasome injury via activation of autophagy flux in Parkinson's disease.

Parkinson's disease (PD) is one of the most common and complex Neurodegeneration, with an inherited metabolic disorder. Fibroblast growth factor 21 (FGF21), an endocrine hormone that belongs to the fibroblast growth factor superfamily, plays an extensive role in metabolic regulation. However, our understandings of the specific function and mechanisms of FGF21 on PD are still quite limited. Here, we aimed to elucidate the actions and the underlying mechanisms of FGF21 on dopaminergic neurodegeneration using cellular models of parkinsonism. To investigate the effects of FGF21 on dopaminergic neurodegeneration in vitro, proteasome impairment models of PD were utilized. Human dopaminergic neuroblastoma SH-SY5Y cells were treated with the proteasome inhibitor lactacystin (5 μmol/L) for 12h, then with 50ng/ml FGF-21 with or without 5 mmol/L of 3-methyladenine.The cells were dissected to assess alterations in autophagy using immunofluorescence, immunoblotting and electron microscopy assays. Our data indicate that FGF21 prevents dopaminergic neuron loss and shows beneficial effects against proteasome impairment induced PD syndrome, indicating it might be a potent candidate for developing novel drugs to deal with PD.

Fibroblast growth factor 1 ameliorates thin endometrium in rats through activation of the autophagic pathway.

Background: Thin endometrium is a reproductive disorder that affects embryo implantation. There are several therapies available for this disease, however they are not so effective. Fibroblast growth factor 1 (FGF1) is a member of fibroblast growth factor superfamily (FGFs), and it has been demonstrated that FGF1 expression was altered in samples collected from patients with thin endometrium. However, it is unclear if FGF1 could improve thin endometrium. The aim of this study was to investigate whether FGF1 have a therapeutic effect on thin endometrium. Methods: A model of thin endometrium induced by ethanol was constructed to investigate the effect and mechanism of action of FGF1 in thin endometrium. In the characterization experiments, 6-8 weeks female rats (n = 40) were divided into four groups: i) Control group; ii) Sham group; iii) Injured group; (iv) FGF1 therapy group. Endometrial tissues would be removed after three sexuel cycles after molding. Morphology and histology of the endometrium were evaluated by visual and hematoxylin and eosin staining. Masson staining and expression of α-SMA in endometrium showed the degree of endometrial fibrosis. Western blotting (PCNA、vWF and Vim) and immunohistochemistry (CK19 and MUC-1) demonstrated the effect of FGF1 on cell proliferation and angiogenesis. Moreover, immunohistochemistry (ER and PR) was used to explore the function of endometrium. The remaining rats (n = 36) were divided into three groups: i) Injured group; ii) FGF1 therapy group; and iii) 3-methyladenine. Western blotting (p38、p-p38、PI3K 、SQSTM1/p62、beclin-1 and LC3) was used to explore the mechanisms of FGF1. Results: In FGF1 therapy group, the morphology and histology of endometrium improved compared with the model group. Masson staining and the expression level of α-SMA showed that FGF1 could decrease the fibrotic area of endometrium. Besides, changes in ER and PR expression in the endometrium suggested that FGF1 could restore endometrium-related functions. Western blotting and immunohistochemistry revealed that PCNA, vWF, Vim, CK19 and MUC-1 were significantly increased after FGF1 treatment compared with the thin endometrium. In addition, Western blotting showed that p38, p-p38, PI3K, SQSTM1/p62, beclin-1 and LC3 levels were higher in FGF1 group than in the injured group. Conclusion: FGF1 application cured the thin endometrium caused by ethanol through autophagy mechanism.

Five SNPs Within the FGF5 Gene Significantly Affect Both Wool Traits and Growth Performance in Fine-Wool Sheep (Ovis aries).

Fibroblast growth factor 5 (FGF5) gene, a member of fibroblast growth factor superfamily, plays significant roles in the regulation of the hair growth cycle during the development of mammalian hair follicles as well as the skeletal muscle development. In this study, DNA sequencing was used to scan the putative SNPs within the full-length of FGF5 gene, and SNPscan high-throughput technique was applied in the individual genotyping of 604 crossbred sheep. 10 SNPs were identified within FGF5 gene while five of them located in intron 1 could be genotyped, namely SNP1 (g. 105914953 G > A), SNP2 (g. 105922232 T > C), SNP3 (g. 105922244 A > G), SNP4 (g. 105922334 A > T) and SNP5 (g. 105922340 G > T). All these SNPs were in accord with the Hardy-Weinberg equilibrium (P > 0.05), and displayed the moderate polymorphism with PIC values ranging from 0.302 to 0.374. Thereafter, the correlation analysis between each SNP locus and economic traits including wool length, greasy wool weight and growth performance of sheep was systematically implemented. In our results, SNP1, SNP3, SNP4 and SNP5 were significantly associated with wool length, greasy wool weight and growth traits of SG sheep (P < 0.05); SNP1, SNP2, SNP3, and SNP4 were significantly correlated with wool length and growth traits of SSG sheep (P < 0.05). Meanwhile, our study revealed a strong linkage disequilibrium (LD) relationship among these SNPs (r2 > 0.33), except for SNP3 and SNP4 sites (r2 = 0.30). Combination genotype analysis showed that combination genotypes were significantly associated with mean fiber diameter of SG (P < 0.05), and body weight trait of SSG (P < 0.01). The above findings suggested that these SNP loci might affect economic traits synergistically and could be regarded as potential molecular markers for improving both wool production and growth performance of fine-wool sheep, which lay a molecular foundation for the breeding of fine dual-purpose sheep thereby accelerating the pace of sheep breeding.

Potential therapeutic role of fibroblast growth factor 21 in neurodegeneration: Evidence for ameliorating parkinsonism via silent information regulator 2 homolog 1 and implication for gene therapy

Parkinson's disease (PD) is one of the common complex neurodegenerative diseases and characterized by abnormal metabolic brain networks. Fibroblast growth factor 21 (FGF21), an endocrine hormone that belongs to the fibroblast growth factor superfamily, plays an extensive role in the regulation of metabolism. However, our understandings of the specific function and mechanisms of FGF21 on PD are still quite limited. Here we aimed to elucidate the actions and the underlying mechanisms of FGF21 on dopaminergic neurodegeneration using cellular and animal models of parkinsonism. To investigate the effects of FGF21 on dopaminergic neurodegeneration in vivo and in vitro, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine models of PD were utilized, and animals were treated with recombinant FGF21 protein or FGF21 gene delivered via an adeno-associated virus. In the present study, systemic and continuous intracerebroventricular recombinant FGF21 protein administration to mice both prevented behavioral deficits, protected dopaminergic neurons against degeneration, and ameliorated α-synuclein pathology in PD models; and in vivo gene delivery of FGF21 improved PD-like symptoms and pathologies suggesting a potential implication of FGF21 in gene therapy for PD. In vitro evidence confirmed FGF21 mediated neuroprotective benefits against PD pathologies. Further, our data suggested that enhanced autophagy was involved in the FGF21 neuroprotection in PD models, and silent information regulator 2 homolog 1 may play a crucial role in molecular mechanisms underlying anti-PD activities of FGF21.

FHF1 is a bona fide fibroblast growth factor that activates cellular signaling in FGFR-dependent manner

Fibroblast growth factors (FGFs) via their receptors (FGFRs) transduce signals from the extracellular space to the cell interior, modulating pivotal cellular processes such as cell proliferation, motility, metabolism and death. FGF superfamily includes a group of fibroblast growth factor homologous factors (FHFs), proteins whose function is still largely unknown. Since FHFs lack the signal sequence for secretion and are unable to induce FGFR-dependent cell proliferation, these proteins were considered as intracellular proteins that are not involved in signal transduction via FGFRs. Here we demonstrate for the first time that FHF1 directly interacts with all four major FGFRs. FHF1 binding causes efficient FGFR activation and initiation of receptor-dependent signaling cascades. However, the biological effect of FHF1 differs from the one elicited by canonical FGFs, as extracellular FHF1 protects cells from apoptosis, but is unable to stimulate cell division. Our data define FHF1 as a FGFR ligand, emphasizing much greater similarity between FHFs and canonical FGFs than previously indicated.81CmN2k-d47mwAPaQtumJyVideo . (MP4 38460 kb)Graphical abstract

Bioinformatics analysis of evolutionary characteristics and biochemical structure of FGF5 Gene in sheep

Fibroblast growth factor (FGF) 5 regulates the development and periodicity of hair follicles, which can affect hair traits. Loss-of-function mutations associated with long-hair phenotypes have been described in several mammalian species. Sheep is an important economic animal, however, the evolution characterizations and biological mechanism of oFGF5 (Ovis aries FGF5) gene are still poorly understood. In this study, oFGF5 gene was obtained by resequencing the whole genome of three Dorper sheep and RACE of two Kazakh sheep FGF5. We proposed FGF5 was phylogenetically related to FGF4 family and oFGF5 clearly orthologed to goat FGF5. Six loci were found from the positive selection results of FGF5 and half of them located on signal peptide. The basically similar rates of function-altering substitutions in sheep and goat lineage and the rest of the mammalian lineage of 365 SNPs indicated that the FGF5 gene was quite conservative during evolution. Homology modeling of the oFGF5 suggested that it has a highly conserved FGF superfamily domain containing 10 β-strands. Furthermore, the protein–protein docking analysis revealed that oFGF5 have the potential to form heterodimers with oFGFR1, the predicted interaction interface of FGF5-FGFR1 heterodimer was formed mainly by residues from FGF superfamily domain. Our observations suggested the evolutionary and structural biology features of oFGF5 might be relevant to its function about hair follicle development and modulating hair growth, and we confirmed our speculation by using the FGF5 gene editing sheep produced by CRISPR/Cas9 technology.

FGF11 influences 3T3‐L1 preadipocyte differentiation by modulating the expression of PPARγ regulators

Fibroblast growth factor 11 (FGF11) is a member of the intracellular fibroblast growth factor superfamily. Here, we identified FGF11 as a novel mediator of adipogenesis. During 3T3‐L1 adipocyte differentiation, the expression of FGF11 decreased at the mitotic clonal expansion stage and increased at the terminal differentiation stage. FGF11 knockdown reduced the expression of peroxisome proliferator‐activated receptor gamma (PPARγ), a master regulator of adipogenesis, resulting in the inhibition of adipocyte differentiation. Treatment with the PPARγ agonist rosiglitazone restored the inhibition of adipogenesis caused by FGF11 knockdown. We also report that the expression of the PPARγ regulators CCAAT/enhancer‐binding protein α, sterol regulatory element‐binding protein 1, KLF9, KLF2, GATA binding factor 2, and GATA binding factor 3 was influenced by FGF11. These results suggest that FGF11 indirectly controls the expression of PPARγ through modifying the expression of multiple PPARγ regulators, thereby mediating adipogenesis.

Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters.

Alpha-Klotho is a member of the Klotho family consisting of two other single-pass transmembrane proteins: βKlotho and γKlotho; αKlotho has been shown to circulate in the blood. Fibroblast growth factor (FGF)23 is a member of the FGF superfamily of 22 genes/proteins. αKlotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling including regulation of phosphate metabolism. The extracellular domain of transmembrane αKlotho is shed by secretases and released into blood circulation (soluble αKlotho). Soluble αKlotho has both FGF23-independent and FGF23-dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interaction with other calciophosphotropic hormones such as PTH and 1,25-(OH)2D. The direct role of αKlotho and FGF23 in the maintenance of phosphate homeostasis is partly mediated by modulation of type II Na+-dependent phosphate co-transporters in target organs. αKlotho and FGF23 are principal phosphotropic hormones, and the manipulation of the αKlotho-FGF23 axis is a novel therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess and αKlotho deficiency such as chronic kidney disease.

Parsing the Potential Neuroendocrine Actions of FGF21 in Primates.

Fibroblast growth factor (FGF) 21, a unique, largely liver-derived endocrine member of the FGF superfamily, is often thought of as a fasting factor owing to its induction in rodents during starvation. However, FGF21 is not increased by fasting for periods of <7 days in humans; instead, it rises sharply after acute alcohol and sugar intake and also after several days of overfeeding, suggesting another role in states of positive energy balance. Recent studies suggest that in the postingestive state, FGF21 may regulate energy intake and discourage consumption of alcohol and sugars, most likely through effector circuits in the central nervous system. FGF21 also increases fat oxidation in the liver, improves markers of insulin sensitivity, and stimulates adiponectin production. Thus, in primates, FGF21 may defend against hepatic nutrient overload by promoting adaptations that reduce ectopic lipid storage, including inhibiting sugar and alcohol appetite and promoting lipid sequestration in adipose tissue.

The Potential Role of Fibroblast Growth Factor 21 in Lipid Metabolism and Hypertension

Fibroblast growth factor (FGF) 21 belongs to the FGF superfamily that is involved in cell proliferation and differentiation, neural development, angiogenesis, and metabolism. FGF21 requires β-Klotho as a co-receptor. Tissues involved in metabolism such as the liver, adipose tissues, skeletal muscle, and pancreas express FGF21. Starvation increases hepatic expression of FGF21, which then acts centrally to increase hepatic gluconeogenesis. FGF21 also increases fatty acid oxidation. This may be relevant in cold exposure, when expression of FGF21 is induced. Chronic treatment with recombinant FGF21 reduces serum and hepatic triglyceride levels and ameliorates fatty liver in obese mice, through the suppression of the lipogenic gene, Srebp-1. FGF21 reduces hepatic cholesterol production by inhibiting Srebp-2, a transactivator of proprotein convertase subtilisin/kexin type 9 (PCSK9). LY2045319, an FGF21 analog, reduces LDL-C and triglycerides and increases HDL-C in obese human subjects with type 2 diabetes. FGF21 does not seem to lower blood pressure acutely. In rats fed with high-fructose water to induce mild hypertension, 4-week treatment with recombinant FGF21 led to normalization of systolic blood pressure and improved serum lipid profile. FGF receptors and β-Klotho are expressed on the nucleus tractus solitarii and nodose ganglion in the baroreflex afferent pathway. Moreover, FGF21 acts on the hypothalamus to release corticosterone and induces in adipocytes the production of adiponectin, an adipokine with antihypertensive activities. Therefore, FGF21 may decrease blood pressure indirectly, through its actions in the liver, brain, and adipose tissues.

Fibroblast growth factor 21 night watch: advances and uncertainties in the field.

Fibroblast growth factor (FGF) 21 belongs to a hormone-like subgroup within the FGF superfamily. The members of this subfamily, FGF19, FGF21 and FGF23, are characterized by their reduced binding affinity for heparin that enables them to be transported in the circulation and function in an endocrine manner. It is likely that FGF21 also acts in an autocrine and paracrine fashion, as multiple organs can produce this protein and its plasma concentration seems to be below the level necessary to induce a pharmacological effect. FGF21 signals via FGF receptors, but for efficient receptor engagement it requires a cofactor, membrane-spanning βKlotho (KLB). The regulation of glucose uptake in adipocytes was the initial biological activity ascribed to FGF21, but this hormone is now recognized to stimulate many other pathways in vitro and display multiple pharmacological effects in metabolically compromised animals and humans. Understanding of the precise physiology of FGF21 and its potential medicinal role has evolved exponentially over the last decade, yet numerous aspects remain to be defined and others are a source of debate. Here we provide a historical overview of the advances in FGF21 biology focusing on the uncertainties in the mechanism of action as well as the differing viewpoints relating to this intriguing protein.

FGF21 protects against ox-LDL induced apoptosis through suppressing CHOP expression in THP1 macrophage derived foam cells.

BackgroundFGF21,as a member of the fibroblast growth factor superfamily, is an important endogenous regulator to systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. The formation and apoptosis of foam cell, induced by ox-LDL and oxysterols, are key steps in the development of atherosclerosis.MethodsIn this study, THP1 derived macrophages were induced into foam cells by ox-LDL or sterols. The formation and apoptosis of foam cells treated with or without FGF21 were analyzed.ResultsWe demonstrated that the accumulation of cholesterol was decreased after FGF21 treatment in THP1 macrophage derived foam cells. Consistently, the apoptosis of macrophage was alleviated dramatically with FGF21 treatment. ERK1/2 knockdown didn’t abrogate the effect of FGF21 on THP1 macrophage derived foam cells. However, FGF21 suppressed the induced expression of CHOP and DR5 in THP1 macrophage derived foam cells.ConclusionFGF21 protects against the formation and apoptosis of THP1 macrophages derived foam cells through suppressing the expression of CHOP.

FGF21 increases cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells.

FGF21, a member of the fibroblast growth factor superfamily, is an important endogenous regulator of systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. However, whether FGF21 is associated with atherosclerotic diseases remains unclear. In this study, the effects of FGF21 on cholesterol efflux in THP1 macrophage-derived foam cells and the underlying mechanisms were investigated. THP1 macrophage-derived foam cells were incubated with 0, 25, 50, 100, 200, and 400 ng/mL of FGF21 for varying time periods (0, 6, 12, and 24 h). Cholesterol efflux onto apoA-1 was assessed by high-performance liquid chromatography assays, while change in ABCA1 expression was analyzed by western blot and real-time quantitative PCR. Incubation was performed with the ERK1/2-specific inhibitor PD98059, PPARγ-specific inhibitor GW9662, and LXRα siRNA. Our results show that FGF21 promotes cholesterol efflux and ABCA1 expression in THP1 macrophage-derived foam cells in a dose- and time-dependent manner. In addition, inhibition of ERK1/2 or PPARγ, or knockdown of LXRα attenuated FGF21-mediated promotion of ABCA1 expression and cholesterol efflux. These results demonstrate that FGF21 can promote cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells.

Commentary (Research Highlights)

Putting a Finger on Neurotrophic Protein Therapy in Parkinson's Disease Parkinson's disease (PD) was first described in the essay entitled “An Essay of the Shaking Palsy” by James Parkinson in 1817. PD is the most common neurodegenerative movement disorder, whose neuropathological hallmarks are characterized by progressive and profound loss of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta with the presence of eosinophilic intracytoplasmic, proteinaceous inclusions termed Lewy bodies and dystrophic Lewy neurites in surviving neurons. Although neuronal cell loss in the substantia nigra pars compacta is pronounced, there is widespread neurodegeneration in the CNS with the pars compacta being involved in midstages of the disease. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity, along with non-motoric symptoms like autonomic, cognitive, and psychiatric problems. As with many multifactorial diseases, the incidence of PD increases with age. Because of an aging population, improved diagnosis, and prolonged survival, especially in developing countries, the number of patients suffering from PD is predicted to double by the year 2030. The power of neurotrophic factors to regulate neuronal cell survival in the developing nervous system and to promote also survival after injury or protect neurons in toxin-mediated disease models in animals has encouraged the idea that such proteins could be harnessed for the treatment of neurodegenerative disease. In the case of dopaminergic neurons, glial cell line-derived neurotrophic factor (GDNF), a member of the basic fibroblast growth factor superfamily, given intracerebrally has neuroprotective and neurorestorative effects in neurotoxin-induced rodent and non-human primate models of PD. In spite of extensive positive preclinical data and encouraging results from phase I clinical trials, results from phase II studies have been disappointing. Indeed, neurotrophic factor treatment of CNS diseases presents an especially complex problem, since these polypeptides have poor pharmacokinetics and bioavailability and are not able to cross the blood-brain barrier. At the same time, excessive levels of a neurotrophic protein may provoke deleterious side-effects, as evidenced by toxicity (including multifocal cerebellar Purkinje cell loss) observed in rhesus monkeys that received intraputamenal infusion of high concentrations of GDNF. A novel approach to this problem has recently been reported by Laganiere and colleagues, who explored the possibility of engineering zinc finger protein transcription factors (ZFP TFs) that activate the expression of the endogenous GDNF gene. Transcription factors based on Cys2-His2 ZFPs can be engineered to specifically target virtually any gene. By targeting the endogenous gene and exploiting the native promoter, which imposes a physiological upper limit on the level of gene expression from each allele, a ZPF can produce sufficient, but not supraphysiological levels of the therapeutic protein needed to achieve both long-term efficacy and safety. Laganiere et al. designed a human GDNF ZFP TF (hGDNF-ZFP) that recognized a site that is fully conserved between human and rhesus macaque. Having confirmed that hGDNF-ZFP activated rhesus GDNF in rhesus macaque cell lines, the authors then designed and assembled a panel of ZFP activators specific to the rat GDNF promoter. Using an adeno-associated viral vector serotype 2 as the delivery vehicle, the engineered transcription factor that gave the highest levels of rat GDNF activation was tested in the rat 6-hydroxydopamine model of PD. Vector was infused bilaterally into the striatum by convection-enhanced delivery. The modest (∼60%) overall increase in striatal GDNF levels provoked by the ZFP was sufficient to provide marked improvement in all behavioral tests performed. Moreover, functional neuroprotection by the GDNF activator was supported by immunohistochemical demonstration of preservation of tyrosine hydroxylase-positive nigrostriatal neurons. While activation of endogenous GDNF was adequate to protect again neurotoxin lesion in rat, demonstration of efficacy and safety in a nonhuman primate model of PD will be a prerequisite before advancing the ZFP-based approach to the clinic. The dual species-specific GDNF activator should facilitate such studies. In addition, convection-enhanced delivery is expected to provide a more complete coverage of the putamen, unlike previously used infusion protocols. Engineered ZFP activators that drive specific activation of endogenous GDNF combined with highly efficient convection-enhanced delivery may well offer hope to realize the therapeutic potential of GDNF.

Extending the family table: Insights from beyond vertebrates into the regulation of embryonic development by FGFs

Since the discovery of fibroblast growth factors (FGFs) much focus has been placed on elucidating the roles for each vertebrate FGF ligand, receptor, and regulating molecules in the context of vertebrate development, human disorders and cancer. Studies in human, mouse, frog, chick, and zebrafish have made great contributions to our understanding of the role of FGFs in specific processes. However, in recent years, as more genomes are sequenced, information is becoming available from many non-vertebrate models and a more complete picture of the FGF superfamily as a whole is emerging. In some cases, less redundancy in these FGF signaling systems may allow for more mechanistic insights. Studies in sea anemones have highlighted how ancient FGF signaling is and helped provide insight into the evolution of the FGF gene family. Work in nematodes has shown that different splice forms can be used for functional specificity in invertebrate FGF signaling. Comparing FGFs between urochordates and vertebrates as well as between different insect species reveals important clues into the process of gene loss, duplication and subfunctionalization of FGFs throughout evolution. Finally, comparing all members of the FGF ligand superfamily reveals variability in many properties, which may point to a feature of FGFs as being highly adaptable with regards to protein structure and signaling mechanism. Further studies on FGF signaling outside of vertebrates is likely to continue to complement work in vertebrates by contributing additional insights to the FGF field and providing unexpected information that could be used for medical applications.

Fibroblast growth factor (FGF)-21 signals through both FGF receptor-1 and 2

Fibroblast growth factor (FGF)-21 is a member of the FGF superfamily based on sequence homology. However, unlike most members of this family it does not show any mitogenic activity in all cell types tested. The objective of this study is to identify and characterize receptors for this molecule. Sequencing of the cDNA clones from 3T3-L1 adipocytes indicates that the only isoforms for FGFR-1 and 2 expressed in 3T3-L1 cells are 1IIIc and 2IIIc, respectively, suggesting that FGF-21 regulates glucose metabolism in 3T3-L1 adipocytes through FGFR-1IIIc and FGFR-2IIIc.

Pleiotropic function of FGF‐4: Its role in development and stem cells

Fibroblast growth factors (FGFs) were initially recognized as fibroblast-specific growth factor, and it is now apparent that these growth factors regulate multiple biological functions. The diversity of FGFs function is paralleled by the emerging diversity of interactions between FGF ligands and their receptors. FGF-4 is a member of the FGF superfamily and is a mitogen exhibiting strong action on numerous different cell types. It plays a role in various stages of development and morphogenesis, as well as in a variety of biological processes. Recent studies reveal the molecular mechanisms of FGF-4 gene regulation in mammalian cells, which is involved in the developmental process. Furthermore, FGF-4 also acts on the regulation of proliferation and differentiation in embryonic stem cells and tissue stem cells. In this review, we focus on the diverse biological functions of FGF-4 in the developmental process and also discuss its putative roles in stem cell biology.

Exposure to Organophosphates Reduces the Expression of Neurotrophic Factors in Neonatal Rat Brain Regions: Similarities and Differences in the Effects of Chlorpyrifos and Diazinon on the Fibroblast Growth Factor Superfamily

BackgroundThe fibroblast growth factor (FGF) superfamily of neurotrophic factors plays critical roles in neural cell development, brain assembly, and recovery from neuronal injury.ObjectivesWe administered two organophosphate pesticides, chlorpyrifos and diazinon, to neonatal rats on postnatal days 1–4, using doses below the threshold for systemic toxicity or growth impairment, and spanning the threshold for barely detectable cholinesterase inhibition: 1 mg/kg/day chlorpyrifos and 1 or 2 mg/kg/day diazinon.MethodsUsing microarrays, we then examined the regional expression of mRNAs encoding the FGFs and their receptors (FGFRs) in the forebrain and brain stem.ResultsChlorpyrifos and diazinon both markedly suppressed fgf20 expression in the forebrain and fgf2 in the brain stem, while elevating brain stem fgfr4 and evoking a small deficit in brain stem fgf22. However, they differed in that the effects on fgf2 and fgfr4 were significantly larger for diazinon, and the two agents also showed dissimilar, smaller effects on fgf11, fgf14, and fgfr1.ConclusionsThe fact that there are similarities but also notable disparities in the responses to chlorpyrifos and diazinon, and that robust effects were seen even at doses that do not inhibit cholinesterase, supports the idea that organophosphates differ in their propensity to elicit developmental neurotoxicity, unrelated to their anticholinesterase activity. Effects on neurotrophic factors provide a mechanistic link between organophosphate injury to developing neurons and the eventual, adverse neurodevelopmental outcomes.

Sevelamer Hydrochloride and Calcium Bicarbonate Reduce Serum Fibroblast Growth Factor 23 Levels in Dialysis Patients

Fibroblast growth factor 23 (FGF23) is a member of the fibroblast growth factor superfamily which displays a strong phosphaturic action and an inhibition of vitamin D 1-alpha hydroxylase activity. Fourty-six patients undergoing maintenance hemodialysis therapy participated in the study. They were randomly divided into 2 groups, and treated with either 3 g sevelamer hydrochloride+3 g of calcium bicarbonate (CaCO3), or 3 g of CaCO3 alone. Serum FGF23 levels were determined by a sandwich enzyme-linked immunosorbent assay (ELISA) system that detects the intact form of FGF23 molecules. Although the serum inorganic phosphate (Pi) levels were comparable before treatment, the levels were significantly lower in the patients treated with sevelamer hydrochloride+CaCO3 than those with CaCO3 alone after 4 weeks of treatment (P<0.05). Serum FGF23 levels significantly decreased after 4 weeks of the treatment with sevelamer hydrochloride+CaCO3 from the pretreatment levels (P<0.05), while no changes were found in the patients treated with CaCO3 alone. Thus, the use of sevelamer hydrochloride and CaCO3 reduced serum FGF23 levels in dialysis patients presumably through inhibiting phosphate load into the intestine.

Prostaglandin E2 Stimulates Fibronectin Expression through EP1 Receptor, Phospholipase C, Protein Kinase Cα, and c-Src Pathway in Primary Cultured Rat Osteoblasts

Fibronectin (Fn) is involved in the early stages of bone formation, and prostaglandin E (PGE) is an important factor regulating osteogenesis. Here we found that PGE(2) enhanced extracellular Fn assembly in rat primary osteoblasts, as shown by immunofluorescence staining and enzyme-linked immunosorbent assay. PGE(2) also increased the protein levels of Fn by using Western blotting analysis. By using pharmacological inhibitors or activators or genetic inhibition by the EP receptor, antisense oligonucleotides revealed that the EP(1) receptor but not other PGE receptors is involved in PGE(2)-mediated up-regulation of Fn. At the mechanistic level, Ca(2+) chelator (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester)), phosphatidylinositol-phospholipase C inhibitor (U73122), or Src inhibitor (PP2) attenuated the PGE(2)-induced Fn expression. Protein kinase C (PKC) inhibitor (GF109203X) also inhibited the potentiating action of PGE(2). Furthermore, treatment with antisense oligonucleotides of various PKC isoforms, including alpha, beta, epsilon, and delta, demonstrated that alpha isozyme plays an important role in the enhancement action of PGE(2) on Fn assembly. Flow cytometry and reverse transcription-PCR showed that PGE(2) and 17-phenyl trinor PGE(2) (EP(1)/EP(3) agonist) increased the surface expression and mRNA level of alpha5 or beta1 integrins. Fn promoter activity was enhanced by PGE(2) and 17-phenyl trinor PGE(2) in cells transfected with pGL2F1900-Luc. Cotransfection with dominant negative mutants of PKCalpha or c-Src inhibited the potentiating action of PGE(2) on Fn promoter activity. Local administration of PGE(2) or 17-phenyl trinor PGE(2) into the metaphysis of the tibia via the implantation of a needle cannula significantly increased the Fn and alpha5beta1 integrin immunostaining and bone volume of secondary spongiosa in tibia. Taken together, our results provided evidence that PGE(2) increased Fn and promoted bone formation in rat osteoblasts via the EP(1)/phospholipase C/PKCalpha/c-Src signaling pathway.