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PubMed1999

Spatially discrete FGF-mediated signalling directs glial morphogenesis.

Neurons provide critical signals that regulate both the number and differentiation of glia. In addition, glia are attracted to and enwrap neuronal axonal processes. FGF-like signalling is thought to be one of the many potential axon-derived morphogenetic signals, however, the multiple roles of FGFs have made experimental tests of these signals difficult in vivo. In the Drosophila FGF receptor mutant heartless, glia migrate to axons, but fail to elongate around them. This study shows that in the similar but larger grasshopper CNS, FGF signalling is likely to mediate one step in the close interaction between glia and axons. FGF2-coated beads attract glia in the CNS and compete with axons for their resident, enwrapped glia. In addition, bath applied FGF2 causes mature axonal glia, which normally enwrap axon tracts, to round up. FGF2 activates the product of the grasshopper heartless FGF receptor gene and probably interferes with the normal function of an endogenous axon-associated FGF-like molecule. It is proposed that insect axons provide a critical spatially restricted FGF-like signal that induces glia to enwrap them.

Animals↗
PubMed1999

Graded interference with FGF signalling reveals its dorsoventral asymmetry at the mid-hindbrain boundary.

Signalling by fibroblast growth factors (FGFs) at the mid-hindbrain boundary (MHB) is of central importance for anteroposterior neural patterning from the isthmic organiser. Graded suppression of FGF signalling by increasing amounts of a dominant negative FGF receptor provides evidence that in addition to anteroposterior patterning, FGF signalling is also involved in patterning along the dorsoventral axis at the MHB. FGF signalling at the MHB is required for the activation of the HH target gene spalt at the MHB. Our results indicate that FGF signalling mediates the competence of the MHB to activate spalt in response to SHH. This interdependence of the two signalling pathways is also found in the outbudding optic vesicle where HH requires functional FGF signalling to activate spalt in the proximal eye region.

Animals↗
PubMed2000

Integration of FGF and TWIST in calvarial bone and suture development.

Mutations in the FGFR1-FGFR3 and TWIST genes are known to cause craniosynostosis, the former by constitutive activation and the latter by haploinsufficiency. Although clinically achieving the same end result, the premature fusion of the calvarial bones, it is not known whether these genes lie in the same or independent pathways during calvarial bone development and later in suture closure. We have previously shown that Fgfr2c is expressed at the osteogenic fronts of the developing calvarial bones and that, when FGF is applied via beads to the osteogenic fronts, suture closure is accelerated (Kim, H.-J., Rice, D. P. C., Kettunen, P. J. and Thesleff, I. (1998) Development 125, 1241-1251). In order to investigate further the role of FGF signalling during mouse calvarial bone and suture development, we have performed detailed expression analysis of the splicing variants of Fgfr1-Fgfr3 and Fgfr4, as well as their potential ligand Fgf2. The IIIc splice variants of Fgfr1-Fgfr3 as well as the IIIb variant of Fgfr2 being expressed by differentiating osteoblasts at the osteogenic fronts (E15). In comparison to Fgf9, Fgf2 showed a more restricted expression pattern being primarily expressed in the sutural mesenchyme between the osteogenic fronts. We also carried out a detailed expression analysis of the helix-loop-helix factors (HLH) Twist and Id1 during calvaria and suture development (E10-P6). Twist and Id1 were expressed by early preosteoblasts, in patterns that overlapped those of the FGF ligands, but as these cells differentiated their expression dramatically decreased. Signalling pathways were further studied in vitro, in E15 mouse calvarial explants. Beads soaked in FGF2 induced Twist and inhibited Bsp, a marker of functioning osteoblasts. Meanwhile, BMP2 upregulated Id1. Id1 is a dominant negative HLH thought to inhibit basic HLH such as Twist. In Drosophila, the FGF receptor FR1 is known to be downstream of Twist. We demonstrated that in Twist(+/)(-) mice, FGFR2 protein expression was altered. We propose a model of osteoblast differentiation integrating Twist and FGF in the same pathway, in which FGF acts both at early and late stages. Disruption of this pathway may lead to craniosynostosis.

Acrocephalosyndactylia↗
PubMed2001

FGF signals are involved in the differentiation of notochord cells and mesenchyme cells of the ascidian Halocynthia roretzi.

Differentiation of notochord cells and mesenchyme cells of the ascidian Halocynthia roretzi requires interactions with neighboring endodermal cells and previous experiments suggest that these interactions require fibroblast growth factor (FGF). In the present study, we examined the role of FGF in these interactions by disrupting signaling using the dominant negative form of the FGF receptor. An FGF receptor gene of H. roretzi (HrFGFR) is expressed both maternally and zygotically. The maternally expressed transcript was ubiquitously distributed in fertilized eggs and in early embryos. Zygotic expression became evident by the neurula stage and transcripts were detected in epidermal cells of the posterior half of embryos. Synthetic mRNA for the dominant negative form of FGFR, in which the intracellular tyrosine kinase domain was deleted, was injected into fertilized eggs to interfere with the possible function of HRFGFR: Injected eggs cleaved and gastrulated the same as the control embryos. Analyses of the expression of differentiation markers in the experimental embryos indicated that the differentiation of epidermal cells, muscle cells and endodermal cells was not affected significantly. However, manipulated embryos showed downregulation of notochord-specific Brachyury expression and failure of notochord cell differentiation, resulting in the development of tailbud embryos with shorted tails. The expression of an actin gene that is normally expressed in mesenchyme cells was also suppressed. These results suggest that FGF signals are involved in differentiation of notochord cells and mesenchyme cells in Halocynthia embryos. Furthermore, the patterning of a neuron-specific tubulin gene expression was disturbed, suggesting that the formation of the nervous system was directly affected by disrupting FGF signals or indirectly affected due to the disruption of normal notochord formation.

Amino Acid Sequence↗
PubMed1995

FGF inhibits neurite outgrowth over monolayers of astrocytes and fibroblasts expressing transfected cell adhesion molecules.

We have cultured cerebellar neurons on monolayers of cortical astrocytes in control medium or medium containing recombinant basic fibroblast growth factor (FGF). FGF was found to inhibit neurite outgrowth, with a significant effect seen at 0.5 ng/ml and a maximal effect at 10 ng/ml. FGF increased the production of arachidonic acid (AA) in cerebellar neurons, and when added directly to cultures or generated endogenously via activation of phospholipase A2 using melittin, this second messenger could mimic the inhibitory effect of FGF. FGF and AA could also specifically inhibit neurite outgrowth stimulated by three cell adhesion molecules (NCAM, N-cadherin and L1) expressed in transfected fibroblasts, or in the case of L1 bound to a tissue culture substratum. These data demonstrate that, in certain cellular contexts, FGF can act as an inhibitory cue for axonal growth and that arachidonic acid is the second messenger responsible for this activity. We discuss the possibility that arachidonic acid inhibits neurite outgrowth by desensitising the second messenger pathway underlying neuronal responsiveness to cell adhesion molecules.

3T3 Cells↗
PubMed1992

Juvenile nasopharyngeal angiofibroma contain an angiogenic growth factor: basic FGF.

The presence of an angiogenic protein basic fibroblast growth factor (FGF) was established in juvenile nasopharyngeal angiofibroma (JNF). Extracts of these tumors have the capacity to stimulate endothelial cell proliferation. This activity is indistinguishable from basic FGF. The biological activity contained in the extracts binds to heparin-Sepharose columns and is eluted with a characteristic 2 mol sodium chloride. The exact fraction of the biological activity corresponds to the location where an immunoreactive basic FGF can be detected by radioimmunoassay. These same fractions contain an 18,000-d molecule which is identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting with an antibody to basic FGF. Indeed, immunohistochemical studies localize the growth factor to the endothelium of JNF. Although these findings do not establish that basic FGF mediates the development of this angiofibroma, they do support the possibility that the pathogenesis of JNF is associated with the presence of angiogenic factors like basic FGF. If this is the case, a comprehensive study of the etiology of JNF may lead to a better understanding of how locally produced growth factors mediate proliferative disease and how its modification might lead to better treatment on a biological basis.

Adolescent↗
PubMed2003

Axonal regeneration across long gaps in silicone chambers filled with Schwann cells overexpressing high molecular weight FGF-2.

Basic fibroblast growth factor (FGF-2) has been shown to enhance the survival and neurite extension of various types of neurons including spinal ganglion neurons. In addition, endogenous FGF-2 and FGF receptors are upregulated following peripheral nerve lesion in ganglia and at the lesion site. FGF-2 protein is expressed in different isoforms (18 kDa, 21 kDa, 23 kDa) and differentially regulated after nerve injury. In the rat we analyzed the regenerative capacity of the high molecular weight (HMW) FGF-2 isoforms (21/23 kDa) to support the regeneration of the axotomized adult sciatic nerve across long gaps. The nerve stumps were inserted into the opposite ends of a silicone chamber resulting in an interstump gap of 15 mm. Silicone tubes were filled with Matrigel or a mixture of Schwann cells (SC) and Matrigel. SC were prepared from newborn rats and transfected to overexpress HMW FGF-2. Four weeks after the operation procedure, channels were analyzed with regard to tissue cables bridging both nerve stumps and myelinated axons distal to the original proximal nerve stump. Peripheral nerves interposed with HMW Schwann cells displayed significantly enhanced nerve regeneration, with the greatest number of tissue cables containing myelinated axons and the highest number of myelinated axons. These results suggest that a cellular substrate together with a source of a trophic factor could be a promising tool to promote nerve regeneration and, therefore, become useful also for a clinical approach to repair long gaps.

Animals↗
PubMed2000

Inhibition of FGF-induced alphaA-crystallin promoter activity in lens epithelial explants by TGFbeta.

PURPOSE: Fibroblast growth factor (FGF) plays a key role in normal lens biology, and recent studies suggest that transforming growth factor (TGF)-beta is involved in the origin of certain forms of cataract. In the current study, the effects of FGF and TGFbeta on alphaA-crystallin promoter activity were investigated. METHODS: Rat lens epithelial explants were cultured with or without growth factors after transfecting with the firefly luciferase reporter gene driven by either the mouse alphaA-crystallin promoter region or a control simian virus (SV)40 promoter. RESULTS: FGF-2, at a concentration that induced lens fiber differentiation, strongly stimulated alphaA-crystallin promoter activity in explants at 3 to 4 days of culture, whereas SV40 promoter control specimens showed no comparable increase. At lower concentrations of FGF, sufficient to induce cell proliferation but not differentiation, there was only a slight increase in alphaA-crystallin promoter activity. Stimulation of alphaA-crystallin promoter activity induced by the fiber-differentiating concentration of FGF was virtually abolished by as little as 25 pg/ml TGFbeta2, but the onset of fiber-specific beta-crystallin accumulation was not prevented at this concentration. Phase-contrast microscopy revealed overt cataractous changes only at concentrations of TGFbeta more than 25 pg/ml. CONCLUSIONS: The stimulation of alphaA-crystallin promoter activity by FGF is consistent with its role in inducing accumulation of crystallins in explants. The blocking effect of TGFbeta on this process, even at a concentration too low to induce obvious pathologic changes, indicates the potential for TGFbeta to disturb alphaA-crystallin gene expression during early fiber differentiation.

Animals↗
PubMed2001

Enhanced FGF-2 movement through human sclera after exposure to latanoprost.

PURPOSE: To determine whether exposure of sclera to latanoprost acid alters transscleral permeation by FGF-2. METHODS: Pieces of human sclera were isolated from donor eyes after death, placed in organ culture, and exposed to 50 to 200 nM latanoprost acid or vehicle for 3 days. Transscleral permeability was then assessed by placing each scleral piece into a Ussing apparatus and measuring the amount of FGF-2 that moves from the orbital side to the uveal side of the scleral piece. Transscleral permeation by 10-kDa tetramethylrhodamine-dextran also was determined, for comparison. RESULTS: Transscleral permeation by FGF-2 through sclera that had been incubated with vehicle was 1.53 +/- 0.86 x 10(-8) cm/sec. Transscleral permeation by 10-kDa tetramethylrhodamine-dextran was 1.04 +/- 0.39 x 10(-6) cm/sec. FGF-2 permeation of sclera exposed to 50, 100, and 200 nM latanoprost acid was increased by an average of 48% +/- 62%, 100% +/- 108%, and 108% +/- 79%, respectively, compared with sclera exposed to vehicle (n = 13; P < 0.05). Scleral permeation by 10-kDa dextran after exposure to 50, 100, or 200 nM latanoprost acid was significantly increased by 42% +/- 36%, 59% +/- 51%, and 65% +/- 49%, respectively (n = 14; P < 0.05). The ratio of dextran to FGF-2 permeation was approximately 90 and did not vary with 50, 100, or 200 nM latanoprost acid (P = 0.93, ANOVA). CONCLUSIONS: Exposure of sclera to latanoprost acid increases transscleral permeation by FGF-2 in human scleral organ cultures. Because this increase parallels the increased scleral permeability caused by dextran, it may reflect a general enhancement of permeability, a possibility that future in vivo studies should explore.

Aged↗
PubMed1999

Technology evaluation: gene therapy (FGF-5), Vical.

Vical, in collaboration with Merck, is developing gene-based therapies, including its 'naked DNA', for the potential treatment of ischemic heart disease. Vical has obtained preclinical data in animal models showing that a gene for a potent growth factor, FGF-5, can be delivered and expressed in coronary arteries stimulating the formation of new blood vessels. This new blood vessel formation may provide supplemental blood flow and necessary cardiac tissue oxygenation in areas of the heart where atherosclerotic blockages are present. Vical anticipates that its FGF-5 gene-based product would be used in conjunction with balloon angioplasty to stimulate new blood vessel formation at the site of the blockage. A series of experiments have been conducted in rats, whereby genes encoding FGF-5 were injected directly into rat heart muscle. The DNA was absorbed and the FGF-5 protein was expressed by cardiac myocytes. Active FGF-5 was released into the extracellular spaces of the heart muscle cells and new blood vessels formed throughout the local area. Quantitative measurements of blood vessel formation indicated that capillary density increased significantly in the hearts of treated rats compared to untreated controls. Further studies are underway to evaluate the persistence of new blood vessels following FGF-5 gene injection, and measurements will be made to assess the extent of improved blood flow in the affected region [177118]. In December 1996, the US patent office issued patent number US-05580859, covering Vical's naked DNA technology [227199].

Animals↗
PubMed2002

Trophic effects of platelets on cultured endothelial cells are mediated by platelet-associated fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF).

In addition to their role in primary hemostasis, platelets serve to support and maintain the vascular endothelium. Platelets contain numerous growth factors including the potent angiogenic inducers VEGF and FGF-2. To characterize the function of these two platelet-associated growth factors, the effects of the addition of purified platelets to cultured endothelial cells were examined. The survival and proliferation of endothelial cells were markedly stimulated (2-3-fold and 5-15-fold respectively) by the addition of gel-filtered platelets. Acetylsalicylic acid-treated or lyophilized fixed-platelets were ineffective in supporting endothelial cell proliferation. In Transwell assays, the stimulatory effect of platelets on endothelial cells was preserved, consistent with an effect mediated by secreted factors. The combined inhibition of VEGF and FGF-2 by neutralizing antibodies, in contrast to inhibition of either alone, abrogated both platelet-induced endothelial cell survival and proliferation. FGF-2 isoforms were detected in platelet lysates, as well as in the releases of agonist-stimulated platelets. Megakaryocytes generated by ex vivo expansion of hematopoietic progenitor cells with kit ligand and thrombopoietin were analyzed for expression of FGF-2. Punctate cytoplasmic staining but no nuclear staining was observed by immunocytochemistry consistent with possible localization of the growth factor to cytoplasmic granules. The addition of platelets to cultured endothelial cells activated extracellular signal-regulated kinase (ERK) in a dose and time-dependent manner. This effect was abrogated by both anti-FGF-2 and anti-VEGF antibody. Since FGF-2 and VEGF are potent angiogenic factors and known endothelial cell survival factors, their release by platelets provides a plausible mechanism for the platelet support of vascular endothelium.

Blood Platelets↗
PubMed2002

Establishment of a rat long-term culture expressing the osteogenic phenotype: dependence on dexamethasone and FGF-2.

Rat stromal bone-marrow cells cultured in the presence of dexamethasone, ascorbic acid, beta-glycerophosphate, and fibroblast growth factor-2 (FGF-2) express the osteogenic phenotype (Pitaru et al., J. Bone Miner. Res. 8:919-929, 1993). The purpose of this study was to establish a long-term homogeneous culture expressing the osteogenic phenotype. The cultures were routinely passaged every 5 days in the absence or presence of either or both dexamethasone and FGF-2, and the cumulative doubling number and the expression of the osteogenic phenotype were determined. Cultures treated with dexamethasone (10(-7) M) ceased proliferation and only upon addition of FGF-2 (3 ng/ml) was a spontaneous immortalization achieved, as expressed by sustained proliferation for about 1 year, with a doubling time of 22 h and more than 300 doublings in 72 passages. Both FGF-2 and dexamethasone are required and act synergistically to maintain cell propagation, alkaline phosphatase expression, and osteocalcin secretion; however, protein content was FGF-2 dependent and the mineralization was dexamethasone dependent. Repetitive single-cell cloning tested the homogeneity and stability of the cells expressing the osteogenic phenotype in these long-term cultures. It was shown that 25% to 50% of subclones derived from clones with an osteogenic phenotype do not further express the osteogenic phenotype. In conclusion, we have established a spontaneously immortalized dexamethasone- and FGF-2-dependent rat stromal bone-marrow-derived long-term culture expressing the osteogenic phenotype. The cultures tend to lose the osteogenic phenotype, and dexamethasone supports the long-term preservation of the osteogenic phenotype.

Alkaline Phosphatase↗
PubMed2003

High levels of CUG-initiated FGF-2 expression cause chromatin compaction, decreased cardiomyocyte mitosis, and cell death.

Fibroblast growth factor 2 (FGF-2) is a multifunctional mitogen present in CUG-and AUG-initiated forms, referred to as 'hi' and 'lo' FGF-2, respectively. We have used an adenoviral vector to express the predominantly nuclear human 'hi' FGF-2 and examined the relationship between expression levels, mitotic entry, cell number and chromatin compaction of cardiac myocytes, over 1-3 days in culture. At a multiplicity of infection (m.o.i.) of 50, levels of 'hi' FGF-2 (assessed by Western blotting) and mitotic index (fraction of myocyte nuclei staining positive for phosphorylated histone H3) paralleled each other, becoming maximal at 2 days. At 200 m.o.i., maximal expression of 'hi' FGF-2 (approximately double that at 50 m.o.i) was achieved at 2 days and coincided with decreased mitotic index and increased chromatin compaction. At 3 days compaction was maximal, mitotic index was minimal, and cell numbers decreased, accompanied by the appearance of DNA laddering, an indicator of apoptosis. Overall, the lower dose of 'hi' FGF-2 and early time points favored a proliferative phenotype while the higher dose, and later time points, promoted chromatin compaction, inhibition of proliferation and cell death.

Adenoviridae↗
PubMed1992

Characterization of [125I]acidic fibroblast growth factor binding to the cloned human fibroblast growth factor receptor, FGF-flg, on NIH 3T3 cell membranes: inhibitory effects of heparin, pertussis toxin and guanine nucleotides.

The present studies were conducted to characterize the specific binding of recombinant human [125I]acidic fibroblast growth factor ([125]aFGF) to the cloned human fibroblast growth factor (FGF) receptor, flg, overexpressed on stably transfected NIH 3T3 mouse fibroblast (NFlg26) cell membranes. In the presence of 5 U/ml of heparin to block [125I]aFGF binding to membrane bound heparan sulfate proteoglycans, specific [125I]aFGF binding was optimal in the presence of 0.2 M NaCl and in a pH range of 7 to 9. [125I]aFGF labeled a single class of recognition sites with high affinity (Kd = 0.27 nM) and limited capacity (apparent maximum binding = 19.5 pmol/mg of protein). A similar estimate of ligand affinity (Kd = 0.25 nM) was determined from association and dissociation rate experiments. aFGF, basic fibroblast growth factor and several glycine-substituted point mutations of aFGF potently inhibited 0.1 nM [125I]aFGF binding. A variety of putative FGF receptor ligands including poly-L-lysines and poly-L-arginines, protamine, suramin and wheat germ agglutinin were shown to have weak or no affinity for the [125I]aFGF recognition site. Additional saturation studies, conducted in the presence of a lower (0.1 U/ml) heparin concentration, indicated that [125I] aFGF labeled both the high affinity (Kd = 0.02 nM) FGF-flg receptor and a separate class of lower affinity (Kd = 2 nM) recognition sites. Pretreatment of NFlg26 cell membranes with pertussis toxin resulted in a heparin-dependent decrease in the binding affinity (Kd values of 0.57-1.15 nM) of [125I]aFGF. Similar pretreatment with cholera toxin did not significantly affect [125I] aFGF binding. Guanine nucleotides were also found to significantly reduce 0.1 nM [125I]aFGF binding in a heparin-dependent fashion. The present data demonstrate that, in the presence of heparin, [125I]aFGF binds with high affinity to the cloned FGF-flg receptor on NFlg26 cell membranes. However, at a low heparin concentration (0.1 U/ml), [125I]aFGF binds to the FGF-flg receptor with higher affinity than was observed in the presence of 5 U/ml of heparin, and also binds a class of lower affinity recognition sites which are consistent with the labeling of cell surface heparan sulfate proteoglycans. The present data also indicate that agents which are known to interfere with receptor/G-protein coupling reduce the binding affinity of [125I]aFGF and suggest that the FGF-flg receptor may be coupled to a G-protein in addition to its intrinsic tyrosine kinase activity.

Binding Sites↗
PubMed2003

[Sensory neuropeptide SP modulating expression of EGF, FGF-2 and their receptors in fibroblasts of granulation in vivo and in vitro].

OBJECTIVE: To study the modulating effect of sensory neuropeptide substance P (SP) on gene expression of epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2) and EGF receptor (EGFR), FGF receptor-1 (FGFR-1) in granulation fibroblast. METHODS: The study consisted of two parts, in vivo and in vitro. In vivo, fifty wistar rats were randomly arranged into capsaicin group and control group. The rats in capsaicin group were subcutaneously injected with neurotoxin dose of capsaicin (50 mg/kg) on the back of the rats to chemically destroy sensory nerves to prevent the release of SP. After one week, full-thickness skin wounds were created on the rats' back. SP content and EGF, EGFR, FGF-2, FGFR-1 gene expression in the granulation tissue were observed using immunohistochemistry and in situ hybridization combined with image analysis on 3rd, 6th, 9th 12th after skin injury, respectively. The experimental procedure in control group were similar with that in capsaicin group except injection with capsaicin. In vitro, SP (10(-9)-10(-5) mol/L) was added into culture medium for cultured fibroblasts from granulation and mRNA expressions of EGF, FGF-2 and their receptors were assayed with RT-PCR. RESULTS: In the present study, immunoreactive stain for SP in granulation tissue were correlated with gene expression of EGF, FGF-2 and their receptors using in situ hybridization in vivo. Once sensory nerves were destroyed and SP release was inhibited in capsaicin group, the gene expression of above growth factors and their receptors were attenuated. SP concentrations in culture medium for upregulation of mRNA expressions of EGF and EGFR in cultured fibroblasts were from 10(-8) mol/L to 10(-6) mol/L and from 10(-6) mol/L to 10(-5) mol/L, respectively. SP concentration was from 10(-9) mol/L to 10(-5) mol/L for upregulation of FGF-2 mRNA expression in cultured fibroblasts and from 10(-6) mol/L to 10(-5) mol/L for upregulation of FGFR-1. CONCLUSION: Sensory neuropeptide SP released from sensory nerve participates in upregulation of gene expressions of EGF, EGF-2 and their receptors in granulation fibroblasts during wound healing.

Animals↗
PubMed2003

Exacerbation of TGF-beta-induced cataract by FGF-2 in cultured rat lenses.

PURPOSE: Culturing rat lenses with transforming growth factor-beta (TGFbeta) results in the formation of anterior, opaque subcapsular plaques which exhibit many of the features of human subcapsular cataract. The present study was undertaken to determine whether this process is influenced by the presence of fibroblast growth factor (FGF), a normal component of the lens environment in situ. METHODS: Rat lenses were cultured for 4-8 days with TGFbeta-2, alone or in combination with FGF-2, PDGF-AA, or the growth factor inhibitors poly(4-styrenesulfonic acid) (PSS) and suramin. Responses were assessed by monitoring opacification, by routine histology and immunolocalization of markers for fibrotic change (a-smooth muscle actin, fibronectin, and type I collagen), or by measuring DNA accumulation in the epithelial region. RESULTS: Supplementing TGFbeta at a barely cataractogenic dose with 2.5-30 ng/ml FGF-2 resulted in a very strong opacification response. The exceptionally large plaques that formed were similar histologically to those induced by TGFbeta alone at higher concentrations and showed immunoreactivity for all markers. PDGF at a concentration equivalent to FGF in terms of proliferative potential did not demonstrate this effect. Addition of either PSS or suramin reduced the opacification response induced by a cataractogenic dose of TGFbeta alone. CONCLUSIONS: FGF has been identified as a factor capable of exacerbating the cataractogenic effects of TGFbeta. Thus FGF inhibitors, as well as TGFbeta inhibitors, have the potential to protect the lens against TGFbeta-induced cataractous changes.

Actins↗
PubMed2005

[Effect of partial dorsal root rhizotomy on expression of GDNF and FGF-2 in spared dorsal root ganglia].

OBJECTIVE: To explore the temporal change on the expression of GDNF and FGF-2 in spared dorsal root ganglia after partial dorsal root rhizotomy. METHODS: Fifteen cats were divided into the normal group, and the partial dorsal root rhizotomy groups. The partial dorsal root rhizotomy groups were sacrificed on day 7 or 14 and the L6 dorsal root ganglia were taken out from each animal and were made into frozen sections 20 microm in thickness respectively. The sections were stained under the same condition using specific GDNF (1 : 500) and FGF-2 (1 : 500) antibody by ABC method. The GDNF and FGF-2 positive large-sized, and medium-small-sized neurons in DRG were counted in each group. All data were analyzed by q test. RESULTS: GDNF immunoreactivity was observed in both large-sized and medium-small-sized DRG neurons. The number of total positive neurons decreased 7 days after partial dorsal root rhizotomy, and was still small after 14 days. Interestingly, the tendency in the number of positive medium-small-sized DRG neurons was just the same as that of total positive neurons while the positive large sized neurons displayed no difference between the 7th day group and the 14th day group, though the number also decreased after operation. FGF-2 immunoreactivity was noted in both large sized and medium-small-sized DRG neurons. After partial dorsal root rhizotomy, the number of total positive neurons decreased on the 7th day and came back to normal level on the 14th day. The number of positive medium-small sized neurons also showed declination followed by escalation, just the same as that of total positive neurons while the number of positive large-sized neurons exhibited no difference between the normal group and the rhizotomy groups. CONCLUSION: Partial dorsal root rhizotomy can lead to continuously declination of total GDNF immunoreactive neurons in spared ganglia, till the 14th day. FGF-2 expression showed declination on the 7th day, but returned to normal level on the 14th day after partial dorsal root rhizotomy. These findings indicate that the expression change of GDNF and FGF-2 after partial dorsal root rhizotomy correlates with the plasticity of spinal cord.

Animals↗
PubMed1991

[FGF and physiopathological implications].

The role of FGF in retinal pathologies can be considered in two respects: 1-as a causative agent (for instance, stimulating aberrant growth or abnormally affecting some aspects of cellular behaviour), or 2-as a possible therapeutic drug (for instance, its ability to rescue neuronal cells from programmed or surgically-induced death), there is evidence for both: the retina, particularly the photoreceptors (PR), seems to be highly succeptible to a host of genetic defects, for instance, in the rat mutant RCS a defect in the pigmented epithelial cells (RPE) leads to the destruction of the PR. Transocular injection of FGF into RCS rats reduces the rate of PR cell loss. On the other hand, we have recently identify a difference in FGF-Receptor cell biology in the RCS mutant which may underline this particular dystrophy. Cultures of purified RPE cells were established from the dystrophic RCS rat and its congenic normal sighted control, and the number and affinity of cell surface FGF-R determined by incubation with 125I-bFGF. Scatchard analysis of the bining data indicated that whereas affinites were in both strains around 60pM, there was a large reduction in receptor number, about 70% in the mutant. Analysis of other FGF/FGF-R criteria, such as mitogenic activity, receptor molecular weight and the profile of FGF degradatoin showed no significant differences between the strains. Thus, defects in the FGF/FGF-R regulating system may actually led to retinal degeneration (RCS rat). But, once again, the underlying principles of FGF mechanisms of action in vivo are at present too incompletely understood to permit rationalization of these various observations.

Animals↗