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PubMed2000

FGF-2-induced imbalance in early embryonic heart cell proliferation: a potential cause of late cardiovascular anomalies.

BACKGROUND: This laboratory previously demonstrated that placement of fibroblast growth factor-2 (FGF-2)-soaked beads adjacent to the developing ventricle at stage 24 caused cardiovascular anomalies by embryonic day 15. We sought to characterize early cellular changes that may suggest mechanisms for the abnormalities observed at day 15. Because levels of both myocyte proliferation and immunohistochemically detectable endogenous FGF-2 begin to decline before stage 24 in untreated embryos, it was of interest to determine whether exogenous FGF-2 might maintain cardiac myocyte proliferation at or near peak levels. METHODS: Chick embryos were incubated to stage 18 (2.8 days), at which time beads soaked in phosphate-buffered saline (PBS) or 100 microg/ml FGF-2 were placed adjacent to the developing ventricle and development was allowed to continue. After 3 days (stage 29), bromodeoxyuridine (BrdU) was applied to mark dividing cells, followed by double fluorescent assessments to detect relative numbers of dividing and nondividing cells. RESULTS: Quantitative image analysis, using Metamorph software, showed that exogenous FGF-2 caused a 62% increase in the overall number of dividing cells (P < 0.01), concomitant with a 25% increase in total cell number (cell density: P < 0.05). Expressed in relative terms, these changes corresponded to a 25% increase in the proliferation labeling index: 30% of all cells were proliferating in FGF-treated hearts, in contrast with only 24% in control hearts. CONCLUSIONS: Taken together, these data suggest that an FGF-induced imbalance in myocardial cell proliferation at early developmental stages of heart development causes cardiovascular anomalies during late embryogenesis.

Abnormalities, Drug-Induced↗
PubMed2000

Pattern of expression of the KGF receptor and its ligands KGF and FGF-10 during postnatal mouse mammary gland development.

The expression of the KGF receptor (KGFR) and its stromal ligands, KGF and FGF-10, was compared during mouse mammary gland development. KGFR expression in mammary parenchyma is maximal in mature virgin mice, declines during pregnancy and lactation, but rises after weaning. The rise in KGFR mRNA in the virgin animal corresponds to parenchymal growth. The fall in KGFR expression in pregnancy is driven by hormone-induced alveolar differentiation since the level of KGFR mRNA is 5-fold higher in isolated ductal cells compared to alveolar cells. KGF and FGF-10 expression patterns differ during ductal development. FGF-10 is also expressed at about a 15-fold higher molar level than KGF. During pregnancy and lactation, expression of KGF and FGF-10 decreases in intact fat pads but is unchanged in parenchyma-free fat pads. Thus, the decrease in KGF and FGF-10 expression observed in intact glands during pregnancy and lactation is not a direct consequence of the changing hormonal milieu but more likely reflects an increase in the ratio of epithelium to stroma. Differences in the level and pattern of expression of mRNA for KGF, FGF-10, and the KGFR during postnatal development of the mouse mammary gland are a result of morphological development, changes in the ratio of stroma to epithelium, and hormonal regulation of cell differentiation. These changes suggest that the biological roles that these growth factors play are regulated by fluctuations in both growth factor and growth factor receptor expression and that KGF and FGF-10 may have different regulatory functions.

Animals↗
PubMed2004

The activation of fibroblast growth factors (FGFs) by glycosaminoglycans: influence of the sulfation pattern on the biological activity of FGF-1.

Six synthetic heparin-like oligosaccharides have been used to investigate the effect of the oligosaccharide sulfation pattern on the stimulation of acidic fibroblast growth factor (FGF-1) induced mitogenesis signaling and the biological significance of FGF-1 trans dimerization in the FGF-1 activation process. It has been found that some molecules with a sulfation pattern that does not contain the internal trisaccharide motif, which has been proposed for high affinity for FGF-1, stimulate FGF-1 more efficiently than those with the structure of the regular region of heparin. In contrast to regular region oligosaccharides, in which the sulfate groups are distributed on both sides of their helical three-dimensional structures, the molecules containing this particular sulfation pattern display the sulfate groups only on one side of the helix. These results and the fact that these oligosaccharides do not promote FGF-1 dimerization according to sedimentation-equilibrium analysis, confirm the importance of negative-charge distribution in the activation process and strongly suggest that FGF dimerization is not a general and absolute requirement for biological activity.

Biotransformation↗
PubMed2004

FGF-2 signaling is sufficient to induce dermal condensations during feather development.

In a previous report, we showed that fibroblast growth factor-2 (FGF-2) is a signal produced by epidermal placode cells during feather development and that this growth factor can induce feathers in scaleless mutant skins that fail to form feathers due to a defective epidermis (Song et al., [1996] Proc Natl Acad Sci USA 93:10246-10249). Here, we test whether FGF-2 is sufficient to induce dermal condensations, structures that normally form under the control of signals from the epidermal placode and are identified on the basis of aggregation of cells, the expression of FGF receptor-1 and bone morphogenetic protein-2 transcripts and the cessation of proliferation of the condensed cells. By using denuded 8-day scaleless dermis as a test system, we have established that FGF-2 is sufficient to induce dermal condensation. We suggest that the primary effect of FGF-2 is an increase in cellular density mediated through cell migration, followed by the expression of dermal condensation-specific genes and cessation of cell proliferation. The FGF-2 effect can be abolished by heparin, suggesting the involvement of heparan sulfate proteoglycans (HSPGs) in growth factor signaling. The spatiotemporal expression of syndecan-3 during feather development suggests that this cell-surface HSPG may be involved in the response of competent embryonic skin dermis to FGF-2.

Animals↗
PubMed1993

Mouse mammary-tumor virus activates Fgf-3/Int-2 less frequently in tumors from virgin than from parous mice.

Tumorigenesis by mouse mammary-tumor virus (MMTV) involves proviral disruption and transcriptional activation of a number of cellular oncogenes, generically termed Int. The frequencies with which different Int genes are activated in different mouse strains can be quite variable, and previous surveys have suggested that insertions at Int-2/Fgf-3 occur primarily in strains that develop pregnancy-dependent mammary tumors. To address this issue, we have determined the relative contributions of 5 known Int genes (Wnt-1, Wnt-3, Fgf-3, Fgf-4 and Int-3) in mammary tumors from virgin BR6 and multiparous BR6, BALB/cfBR6 and RIII mice. Whereas Fgf-3 was implicated in 66%, 80% and 92% of the tumors from the respective parous animals, only 20% of the tumors from virgin mice expressed Fgf-3. This reduced involvement of Fgf-3 was compensated by proviral insertions in Fgf-4, Int-3 and Wnt-3, but the frequency of Wnt-1 activation was relatively constant. These data strengthen the link between Fgf-3 and a pregnancy-dependent phenotype and suggest that, in the strains analyzed, the frequency of Int-gene activation was influenced more by the hormonal status than by the genetic background.

Animals↗
PubMed2002

Hyaluronate-heparin conjugate gels for the delivery of basic fibroblast growth factor (FGF-2).

The stability and activity of recombinant growth factors administered locally for the repair of damaged tissue can be directly influenced by the physical structure and chemical composition of the delivery matrix. This study describes a novel basic fibroblast growth factor-2 (FGF-2) delivery system synthesized by the conjugation of a structure-stabilizing polymer, hyaluronate (HA), with a sulfated glycosaminoglycan, heparin (HP), that has inherent specific binding sites for members of the FGF family. The biopolymers were formed via stable amine or labile imine bonds by coupling amine-modified HA with oxidized heparin. The addition of recombinant human FGF-2 resulted in the rapid binding of FGF-2 to the heparin segment of the hyaluronate-heparin (HAHP) conjugate. The FGF-2 was released in vitro from the imine-bonded (HAHPi) gels in the form of FGF-2-heparin complexes through the hydrolysis of the imine bonds. In contrast, the release of growth factor from the more stable amine-bonded (HAHPa) gels required treatment with free heparin or enzymatic digestion of the hyaluronate segment. Functional analysis of the released FGF-2 showed that the HAHP conjugate gels increased both the stability and activity of the growth factor.

3T3 Cells↗
PubMed2003

Local infusion of FGF-2 enhances bone ingrowth in rabbit chambers in the presence of polyethylene particles.

Osseointegration of porous-coated implants during revision arthroplasty procedures is often impeded due to the presence of residual granuloma, particulate debris, and a sclerotic, dysvascular bone bed. We hypothesized that local infusion of recombinant fibroblast growth factor (FGF-2) would increase bone ingrowth in an in vivo model of tissue differentiation in the rabbit tibia in the presence of phagocytosable polyethylene particles. A drug test chamber (DTC) was implanted in the proximal medial tibial metaphysis of mature rabbits unilaterally. The chamber contained a 1x 1 x 5-mm tunnel for tissue ingrowth, and was connected to an osmotic diffusion pump. FGF-2 was infused at dosages of 0, 0.5, 5, 50, or 500 ng/day for a 3-week period, with subsequent harvesting of the ingrown tissue after each 3-week treatment. The effects of ultrahigh molecular weight polyethylene particles (0.5-microm diameter) on tissue ingrowth were determined by adding particles to the chamber at concentrations of 5.8 x 10(11) (low dose) or 1.7 x 10(12) (high dose) particles/mL, with and without infusion of 50 ng/day of FGF for 3 weeks. The tissue forming in the chamber was harvested after each treatment for histologic processing and morphometric analysis of bone ingrowth. Statistical analysis was performed using parametric tests (ANOVA), nonparametric tests (Kruskal-Wallis test) and post hoc tests. In the absence of particles, infusion of 50 ng FGF-2 per day yielded the greatest amount of bone ingrowth. The high dose of particles suppressed bone ingrowth into the chamber, but the low dose particles did not (p = 0.0002, 95% confidence limits = 9.19-18.80). Infusion of 50 ng FGF-2 per day significantly increased net bone formation in the presence of high-dose UHMWPE particles (p = 0.039, 95% confidence limits = 1.41-6.79). There was a trend for decreased numbers of vitronectin-receptor positive (osteoclast-like) cells with the addition of FGF-2, compared to particles alone (p = 0.08). Local delivery of FGF-2 may prove useful in mitigating the adverse effects of wear debris (e.g., in treating early osteolytic lesions), and facilitating osseointegration of revision total joint replacements in situations where the bone bed is suboptimal and residual particles and granulomatous tissue are present.

Animals↗
PubMedDate not supplied

Enhanced cartilage tissue engineering by sequential exposure of chondrocytes to FGF-2 during 2D expansion and BMP-2 during 3D cultivation.

Bovine calf articular chondrocytes, either primary or expanded in monolayers (2D) with or without 5 ng/ml fibroblast growth factor-2 (FGF-2), were cultured on three-dimensional (3D) biodegradable polyglycolic acid (PGA) scaffolds with or without 10 ng/ml bone morphogenetic protein-2 (BMP-2). Chondrocytes expanded without FGF-2 exhibited high intensity immunostaining for smooth muscle alpha-actin (SMA) and collagen type I and induced shrinkage of the PGA scaffold, thus resembling contractile fibroblasts. Chondrocytes expanded in the presence of FGF-2 and cultured 6 weeks on PGA scaffolds yielded engineered cartilage with 3.7-fold higher cell number, 4.2-fold higher wet weight, and 2.8-fold higher wet weight glycosaminoglycan (GAG) fraction than chondrocytes expanded without FGF-2. Chondrocytes expanded with FGF-2 and cultured on PGA scaffolds in the presence of BMP-2 for 6 weeks yielded engineered cartilage with similar cellularity and size, 1.5-fold higher wet weight GAG fraction, and more homogenous GAG distribution than the corresponding engineered cartilage cultured without BMP-2. The presence of BMP-2 during 3D culture had no apparent effect on primary chondrocytes or those expanded without FGF-2. In summary, the presence of FGF-2 during 2D expansion reduced chondrocyte expression of fibroblastic molecules and induced responsiveness to BMP-2 during 3D cultivation on PGA scaffolds.

Actins↗
PubMed1982

Response of articular chondrocytes to pituitary fibroblast growth factor (FGF).

Rabbit chondrocytes from pooled articular joints have been delineated by their time of attachment to culture flasks after initiation of primary monolayer culture, either attached (48-AT) or floating (48-F) after 48 hours. A general population of chondrocytes (attached after 72 hours, 72-AT) was also studied. The growth-promoting activity of pituitary fibroblast growth factor (FGF) and its effect on sulfated-proteoglycan synthesis was studied on each chondrocyte population in secondary monolayer culture. 3H-thymidine incorporation during a 1-hour pulse was stimulated by FGF (100 ng/ml) in each chondrocyte population. The response of AT-72 chondrocytes to FGF required an additional fetal bovine serum supplement, while 48-F cells responded independent of serum. The response of 48-AT chondrocytes to FGF (100 ng/ml) during a 1-hour pulse with 3H-thymidine was increased in low serum (0.5-2.0%) rather than when high serum (8-10%) was present in the culture medium. FGF reduced 35SO4 incorporation into sulfated-proteoglycans in the 48-AT and 48-F chondrocyte populations, but not in the 72-AT population. The reduction in 35SO4 incorporation in the 48-AT and 48-F chondrocytes was not characterized by alterations in the hydrodynamic size of the sulfated-proteoglycans as measured by Sepharose CL-2B chromatography nor by changes in the types of sulfated-glycosaminoglycans produced. These results indicated that FGF produced quantitative rather than qualitative alterations in chondrocyte sulfated-proteoglycan synthesis. The latter appears uncoupled from the growth-promoting activity of FGF on chondrocytes.

Animals↗
PubMed2005

FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells.

Human mesenchymal stem cells (hMSCs) expanded with and without fibroblast growth factor (FGF) supplementation were compared with respect to their proliferation rate, ability to differentiate along the chondrogenic pathway in vitro, and their gene expression profiles. hMSCs expanded in FGF-supplemented medium were smaller and proliferated more rapidly than hMSCs expanded in control conditions. Chondrogenic cultures made with FGF-treated cells were larger and contain more proteoglycan than those made with control cells. Furthermore, aggregates of FGF-treated cells lacked the collagen type I-positive and collagen type II-negative outer layer characteristic of aggregates of control cells. A total of 358 unique transcripts were differentially expressed in FGF-treated hMSCs. Of these, 150 were upregulated and 208 downregulated. Seventeen percent of these genes affect proliferation. Known genes associated with cellular signaling functions comprised the largest percentage ( approximately 20%) of differentially expressed transcripts. Eighty percent of differentially expressed extracellular matrix-related genes were downregulated. The present findings that FGF-2 enhances proliferation and differentiation of hMSCs adds to a growing body of evidence that cytokines modulate the differentiation potential and, perhaps, the multipotentiality of adult stem cells. With the generation of gene expression profiles of FGF-treated and control cells we have taken the first steps in the elucidation of the molecular mechanism(s) behind these phenomena.

Age Factors↗
PubMed2001

Control of trophectoderm differentiation by inner cell mass-derived fibroblast growth factor-4 in mouse blastocysts and corrective effect of FGF-4 on high glucose-induced trophoblast disruption.

Previous studies have suggested that fibroblast growth factor-4 (FGF-4) may be a paracrine signal used by inner cell mass (ICM) cells to maintain adjacent trophectoderm (TE) cells in an undifferentiated state. In the present work, immunocytochemical analysis of mouse blastocysts confirmed that FGF-4 was predominantly detected in the ICM before and after spreading over a fibronectin-coated culture substrate. Addition of human recombinant FGF-4 did not influence morphological progression, cell allocation and proliferation in ICM and TE lineages or mitosis and karyorhexis frequencies during blastocyst expansion. Addition of FGF-4 to outgrowing blastocysts, in contrast, induced a significant decrease in the surface of the trophoblast outgrowths formed by the TE cells and in the proportion of giant trophoblasts per outgrowth. The fact that blastocysts display excessive trophoblast expansion and spreading over their culture substrate upon pre-exposure to high concentrations of glucose in vitro was used to further assess the regulatory effect of FGF-4. Addition of FGF-4 was indeed found to fully neutralize the disruptive impact of high glucose on trophoblast outgrowths. Altogether, our data indicate that ICM-derived FGF-4 participates actively in the regulation of trophoblast development.

Animals↗
PubMed2002

Androgen receptor expression induces FGF2, FGF-binding protein production, and FGF2 release in prostate carcinoma cells: role of FGF2 in growth, survival, and androgen receptor down-modulation.

BACKGROUND: Alterations in fibroblast growth factors (FGFs) production and/or FGF receptors expression have been described to play key roles in prostate tumor progression, particularly in androgen-independent tumors. However, the role of androgen receptor (AR) in altering FGF-mediated growth and survival of prostatic neoplastic cells has not been completely defined. In this study, we investigated the alterations in FGF2 production and utilization by the PC3 cell line, after transfection with a full-length AR. METHODS: FGF1,2,7, FGF-binding protein (FGF-BP) production and FGF receptor (FGFR) 1-4 expression were investigated by polymerase chain reaction (PCR) and Western blot analysis. RESULTS: De novo AR expression by PC3 cells restores FGFR2 IIIb isoform expression and sensitivity to FGF7 and FGF2. Androgen stimulation induces AR+ PC3 clones to secrete FGF-BP, likely responsible for activation and mobilization from the extracellular matrix of the high amounts of FGF2 produced by the same cells. In addition to the effects on cell proliferation, FGF2 maintains the survival of AR+ PC3 clones through a positive modulation of the Bcl-2 protein and down-modulates AR protein expression, allowing the escape of selected clones from androgen regulation. CONCLUSION: In the presence of an active AR, the combined production of FGF2 and FGF-BP may play an important role in the progression of prostate cancer through the selection of AR- clones expressing high levels of Bcl-2.

Carrier Proteins↗
PubMed2000

Proximal promoter-independent activation of the far-upstream FGF-inducible response element of syndecan-1 gene.

Far upstream enhancers are predicted to act by looping and activating general transcription factors on core promoters and to require proximal promoter sequences for appropriate gene activation in time and space. We have previously described an FGF-inducible response element (FiRE) located far upstream on the syndecan-1 gene. The FiRE is activated specifically by members of the fibroblast growth factor (FGF) family in NIH3T3 cells. Here we describe the requirements of syndecan-1 proximal promoter for the activation of FiRE by FGF-2. Transient and stable transfections revealed that neither proximal promoter SP1 sites nor TATA-box are required for the FGF-2 induced activation of FiRE. Notably, the enhancer is activated in both orientations by FGF-2 even in the absence of proximal promoter. Importantly, removal of the promoter did not affect the growth factor specificity of FiRE. Proximal promoter independent activation of syndecan-1 gene by FGF-2 might be required during development when syndecan-1 proximal promoter needs to be largely attenuated but simultaneous transient and rapid FGF-2 induced transcription is required.

3T3 Cells↗
PubMed2002

FGF-2 increases colony formation, PTH receptor, and IGF-1 mRNA in mouse marrow stromal cells.

FGF-2 stimulates bone formation in vitro and in vivo in rats. However, there are limited studies in mice and no data on the mechanism(s) by which FGF-2 induces bone formation. We assessed whether short-term FGF-2 treatment of marrow stromal cells from young mice would increase alkaline phosphatase-positive (ALP), mineralized colony formation and expression of genes important in osteoblast maturation. Short-term treatment with FGF-2 (0.01-1.0 nM) for the first 3 days of a 14- or 21-day culture period increased the number of ALP mineralized colonies in bone marrow stromal cells. FGF-2 (0.1 nM) increased the mRNAs for type 1 collagen: osteocalcin, runt domain/core binding factor, PTH/PTHR receptor, and insulin-like growth factor 1 (IGF-1) at 14 and 21 days. We conclude that short-term FGF-2 treatment enhances osteoblast maturation in vitro. Furthermore, the anabolic effect of FGF-2 may be attributed in part to regulation of IGF-1 in osteoblasts.

Animals↗
PubMed2002

Role of c-Fyn in FGF-2-mediated tube-like structure formation by murine brain capillary endothelial cells.

Tube formation of endothelial cells is an important step of angiogenesis. However, little is known about the molecular mechanisms underlying growth factor-mediated tube formation by endothelial cells. FGF-2 stimulates tube formation by a murine brain capillary endothelial cell line, IBE cells, when cultured on collagen gels (differentiation-associated culture condition), whereas cells proliferate and migrate without forming tube on fibronectin-coated surface (proliferation/migration-associated condition). To elucidate FGF-2-mediated signal transduction pathways leading to tube formation by endothelial cells, we focused on the contribution of Src family kinases. Src family kinase inhibitor PP2 attenuated FGF-2-induced tube formation. Stable expression of kinase-inactive c-Src in IBE cells demonstrated no dominant negative effect on FGF-2-induced tube formation. In vitro kinase assay revealed that c-Fyn was activated by FGF-2 only in cells cultured on collagen gels. Three independent cell lines, expressing kinase-inactive c-Fyn, all exhibited attenuation of FGF-2-mediated tube formation. However, FGF-2-mediated proliferation or migration was not clearly perturbed in these cells. These results show the first time that c-Fyn plays a pivotal role in tube formation by endothelial cells.

Animals↗
PubMed1993

Embryonic expression of Fgf-6 is restricted to the skeletal muscle lineage.

As part of an ongoing examination of the functions of the fibroblast growth factor (FGF) gene family in mammalian development, we have carried out an RNA in situ hybridization analysis of the Fgf-6 gene in the mouse embryo. In contrast to what has been found for three other members of the FGF gene family, no Fgf-6 RNA was detected in mouse embryos at E6.5 through E8.5. Fgf-6 RNA was first detected in embryos at E9.5 and was localized exclusively in the myotomal compartment of the somite. Similar results were obtained with embryos at E10.5 and E11.5. At E12.5, expression was still detected in the myotome, and also in the region containing the developing muscles of the body wall. By E14.5, Fgf-6 RNA was found in the majority of skeletal muscles in the fetus. These results are discussed in comparison with what is known about the expression patterns of the genes encoding other FGF family members, as well as their high-affinity receptors.

Animals↗
PubMed1999

Cell migration and chick limb development: chemotactic action of FGF-4 and the AER.

Experiments have been carried out to investigate the role of the apical ectodermal ridge (AER) and FGF-4 on the control of cell migration during limb bud morphogenesis. By coupling DiI cell labeling with ectopic implantation of FGF-4 microcarrier beads we have found that FGF-4 acts as a potent and specific chemoattractive agent for mesenchymal cells of the limb bud. The response to FGF-4 is dose dependent in both the number of cells stimulated to migrate and the distance migrated. The cell migration response to FGF-4 appears to be independent of the known inductive activity of FGF-4 on Shh gene expression. We investigated the role of the AER in controlling cell migration by characterizing the migration pattern of DiI-labeled subapical cells during normal limb outgrowth and following partial AER removal. Subapical cells within 75 micrometer of the AER migrate to make contact with the AER and are found intermingled with nonlabeled cells. Thus, the progress zone is dynamic with cells constantly altering their neighbor relationships during limb outgrowth. AER removal studies show that cell migration is AER dependent and that subapical cells redirect their path of migration toward a functional AER. These studies indicate that the AER has a chemoattractive function and regulates patterns of cell migration during limb outgrowth. Our results suggest that the chemoattractive activity of the AER is mediated in part by the production of FGF-4.

Animals↗
PubMed2000

Mesenchyme with fgf-10 expression is responsible for regenerative capacity in Xenopus limb buds.

A young tadpole of an anuran amphibian can completely regenerate an amputated limb, and it exhibits an ontogenetic decline in the ability to regenerate its limbs. However, whether mesenchymal or epidermal tissue is responsible for this decrease of the capacity remains unclear. Moreover, little is known about the molecular interactions between these two tissues during regeneration. The results of this study showed that fgf-10 expression in the limb mesenchymal cells clearly corresponds to the regenerative capacity and that fgf-10 and fgf-8 are synergistically reexpressed in regenerating blastemas. However, neither fgf-10 nor fgf-8 is reexpressed after amputation of a nonregenerative limb. Nevertheless, nonregenerative epidermal tissue can reexpress fgf-8 under the influence of regenerative mesenchyme, as was demonstrated by experiments using a recombinant limb composed of regenerative limb mesenchyme and nonregenerative limb epidermis. Taken together, our data demonstrate that the regenerative capacity depends on mesenchymal tissue and suggest that fgf-10 is likely to be involved in this capacity.

Amino Acid Sequence↗