Application Of Fibroblast Growth Factor Research Articles

Effects of combined application of fibroblast growth factor (FGF)-2 and carbonate apatite for tissue regeneration in a beagle dog model of one-wall periodontal defect

There has been an increasing desire for the development of predictive periodontal regenerative therapy for severe periodontitis. In this study, we investigated the effect of the combined use of fibroblast growth factor-2 (FGF-2), a drug for periodontal regeneration approved in Japan, and carbonated apatite (CO3Ap), bioresorbable and osteoconductive scaffold, on periodontal regeneration in beagle dog model of one-wall periodontal defect (severe intraosseous defect) for 24 weeks in comparison with CO3Ap or vehicle alone. One-wall periodontal defects were created (mesiodistal width×depth: 4×4mm) on the mesial portion of the mandibular first molar (M1) of beagle dogs on both side. Mixture of FGF-2 and CO3Ap, vehicle and CO3Ap, or vehicle alone were administered to the defects and designated as groups FGF-2+CO3Ap, CO3Ap, and control, respectively. To assess the periodontal regeneration, radiographic analysis over time for 24 weeks, and micro computed tomography (μCT) and histological evaluation at 6 and 24 weeks were performed. For the regenerated tissue in the defect site, the mineral content of the FGF-2+CO3Ap group was higher than that of the CO3Ap group in the radiographic analysis at 6-24 weeks. In the context of new bone formation and replacement, the FGF-2+CO3Ap group exhibited significantly greater new bone volume and smaller CO3Ap volume than the CO3Ap group in the μCT analysis at 6 and 24 weeks. Furthermore, the density of the new bone in the FGF-2+CO3Ap group at 24 weeks was similar to those in the control and CO3Ap groups. Histological evaluation revealed that the length of the new periodontal ligament and cementum in the FGF-2+CO3Ap group was greater than that in the CO3Ap group at 6 weeks. We also examined the effect of the combined use of the FGF-2 and CO3Ap on the existing bone adjacent to the defect and demonstrated that the existing bone height and volume in the FGF-2+CO3Ap group remained significantly greater than those in the CO3Ap group. This study demonstrated that the combination of FGF-2 and CO3Ap was effective not only in enhancing new bone formation and replacing scaffold but also in maintaining the existing bone adjacent to the defect site in a beagle dog model of one-wall periodontal defect. Additionally, new periodontal tissues induced by FGF-2 and CO3Ap may follow a maturation process similar to that formed by spontaneous healing. This suggests that the combined use of FGF-2 and CO3Ap would promote periodontal regeneration in severe bony defects of periodontitis patient.

Application of CNTF or FGF-2 increases the number of M2-like macrophages after optic nerve injury in adult Rana pipiens.

We have previously shown that a single application of the growth factors ciliary neurotrophic factor (CNTF) or fibroblast growth factor 2 (FGF-2) to the crushed optic nerve of the frog, Rana pipiens, increases the numbers and elongation rate of regenerating retinal ganglion cell axons. Here we investigate the effects of these factors on the numbers and types of macrophages that invade the regeneration zone. In control PBS-treated nerves, many macrophages are present 100 μm distal to the crush site at 1 week after injury; their numbers halve by 2 weeks. A single application of CNTF at the time of injury triples the numbers of macrophages at 1 week, with this increase compared to control being maintained at 2 weeks. Application of FGF-2 is equally effective at 1 week, but the macrophage numbers have fallen to control levels at 2 weeks. Immunostaining with a pan-macrophage marker, ED1, and a marker for M2-like macrophages, Arg-1, showed that the proportion of the putative M2 phenotype remained at approximately 80% with all treatments. Electron microscopy of the macrophages at 1 week shows strong phagocytic activity with all treatments, with many vacuoles containing axon fragments and membrane debris. At 2 weeks with PBS or FGF-2 treatment the remaining macrophages are less phagocytically active, containing mainly lipid inclusions. With CNTF treatment, at 2 weeks many of the more numerous macrophages are still phagocytosing axonal debris, although they also contain lipid inclusions. We conclude that the increase in macrophage influx seen after growth factor application is beneficial for the regenerating axons, probably due to more extensive removal of degenerating distal axons, but also perhaps to secretion of growth-promoting substances.

The biological behavior optimization of human periodontal ligament stem cells via preconditioning by the combined application of fibroblast growth factor-2 and A83-01 in in vitro culture expansion

BackgroundAs the optimal source of seed cells in periodontal tissue engineering, periodontal ligament stem cells (PDLSCs) have always been researched to improve cell expansion due to their limited resource and spontaneous differentiation in vitro cultivation. Fibroblast growth factor-2 (FGF-2) has been proven to stimulate bone marrow mesenchymal stem cells (BMMSCs) proliferation and maintain their pluripotency when being added to the culture medium. As a small molecule inhibitor of transforming growth factor-beta receptors (TGF-βRs), A83-01 can also promote cell proliferation. Therefore, the aim of this study was to verify whether the combined application of FGF-2 and A83-01 could augment cell quantity and quality during in vitro culture.MethodsPDLSCs were preconditioned with A83-01, FGF-2, or their combination. A cell counting kit-8 (CCK8) assay, cell apoptosis assay, ALP activity assay, Alizarin Red S staining assay, RT-PCR assay, Western blot assay and ELISA were used to determine the sustained effects of different preconditioning strategies on the proliferation, apoptosis, stemness, osteogenic differentiation and paracrine action of PDLSCs.ResultsThe combined application of FGF-2 and A83-01 significantly augmented cell expansion, reduced cell apoptosis, magnified stemness expression, promoted later osteogenic differentiation and mineralization and increased paracrine action of PDLSCs compared with the control. Moreover, the combination presented significant advantages in enhancing proliferation, stemness expression and paracrine action over FGF-2 alone.ConclusionsThe combined application of A83-01 and FGF-2 may be an improved strategy for PDLSCs biological behavior optimization in culture expansion and advantageous for reinforcing proliferation, stemness expression and cytokine secretion over FGF-2 alone.

The short- and long-term adverse effects of FGF-2 on tympanic membrane perforations.

The objective of this study was to investigate the short- and long-term adverse effects of fibroblast growth factor-2 treatment of tympanic membrane perforations. A total of 134 patients with traumatic tympanic membrane perforations were randomly divided into two groups: an observational group and a fibroblast growth factor-2 treatment group. The closure rate, closure time and principal side-effects were compared between the groups at 6 and 12 months. At 6 months, 131 patients were examined to determine healing outcomes and short-term side-effects. The total closure rate differed significantly between the fibroblast growth factor-2 and observational groups (95.5% vs 73.4, p #x003C; 0.01). The fibroblast growth factor-treated group exhibited a significantly shorter closure time than the observational group (11.9±3.1 days vs 52.6 ± 18.1 days, p = 0.00). Three patients with secondary otitis media with effusion, and three with reperforations, were noted in the fibroblast growth factor-2 group. We additionally performed long-term follow-up on 89.1% of the patients in the observational group and 92.5% of the patients in the fibroblast growth factor-2 group; follow-up was performed 16-42 months after perforation closure. Only a small perforation of the pars flaccida developed in the fibroblast growth factor-2 group. No middle ear cholesteatoma was noted in either group. This study suggests that the topical application of fibroblast growth factor-2 to human traumatic tympanic membranes is safe. Otorrhoea was the most common short-term side-effect; other less common side-effects included otitis media with effusion and reperforation. No serious long-term side-effects were found.

Enhancement of rotator cuff tendon–bone healing with fibroblast growth factor 2 impregnated in gelatin hydrogel sheets in a rabbit model

Application of fibroblast growth factor 2 (FGF-2) may improve the healing response after rotator cuff (RC) surgical repair. This study aimed to determine whether FGF-2-impregnated gelatin hydrogel sheet (GHS) incorporation into the bony trough on the greater tuberosity facilitates healing after RC surgical repair in rabbits. We assigned 120 adult male Japanese white rabbits treated with unilateral surgery for supraspinatus tendon repair into the following groups: suture-only group (suture); suture and GHS with phosphate-buffered saline (carrier); suture and GHS with 3 µg of FGF-2 (F3); and suture and GHS with 30 µg of FGF-2 (F30). The effect of FGF-2 was assessed using histologic, biomechanical, and microcomputed tomography evaluations at 2, 6, and 12 weeks. At 12 weeks, loose fibrovascular tissues emerged at the repair site in the suture and carrier groups and dense tendon-like tissues in the F3 and F30 groups, which demonstrated significantly higher ultimate load-to-failure and stress-to-failure at 12 weeks than that in the suture and carrier groups. Microcomputed tomography imaging showed ectopic calcification formation in some specimens from each group. Appearances or frequencies were similar among groups. The histologic and biomechanical effects of FGF-2 on RC healing were obvious at ≥6 weeks postoperatively. FGF-2-impregnated GHS incorporation into the bony trough on the greater tuberosity before RC surgical repair is feasible and results in histologic and biomechanical improvements during RC healing in rabbits. No detrimental effect on ectopic calcification was observed.

Collagen Hydrogel Scaffold and Fibroblast Growth Factor-2 Accelerate Periodontal Healing of Class II Furcation Defects in Dog.

Objective:Collagen hydrogel scaffold exhibits bio-safe properties and facilitates periodontal wound healing. However, regenerated tissue volume is insufficient. Fibroblast growth factor-2 (FGF2) up-regulates cell behaviors and subsequent wound healing. We evaluated whether periodontal wound healing is promoted by application of collagen hydrogel scaffold in combination with FGF2 in furcation defects in beagle dogs.Methods:Collagen hydrogel was fabricated from bovine type I collagen with an ascorbate-copper ion cross-linking system. Collagen hydrogel was mingled with FGF2 and injected into sponge-form collagen. Subsequently, FGF2 (50 µg)/collagen hydrogel scaffold and collagen hydrogel scaffold alone were implanted into class II furcation defects in dogs. In addition, no implantation was performed as a control. Histometric parameters were assessed at 10 days and 4 weeks after surgery.Result:FGF2 application to scaffold promoted considerable cell and tissue ingrowth containing numerous cells and blood vessel-like structure at day 10. At 4 weeks, reconstruction of alveolar bone was stimulated by implantation of scaffold loaded with FGF2. Furthermore, periodontal attachment, consisting of cementum-like tissue, periodontal ligament-like tissue and Sharpey’s fibers, was also repaired, indicating that FGF2-loaded scaffold guided self-assembly and then re-established the function of periodontal organs. Aberrant healing, such as ankylosis and root resorption, was not observed.Conclusion:FGF2-loaded collagen hydrogel scaffold possessed excellent biocompatibility and strongly promoted periodontal tissue engineering, including periodontal attachment re-organization.

Fibroblast Growth Factor-2 Enhanced The Recruitment of Progenitor Cells and Myelin Repair in Experimental Demyelination of Rat Hippocampal Formations.

Hippocampal insults have been observed in multiple sclerosis (MS) patients. Fibroblast growth factor-2 (FGF2) induces neurogenesis in the hippocampus and en- hances the proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPCs). In the current study, we have investigated the effect of FGF2 on the processes of gliotoxin induced demyelination and subsequent remyelination in the hippocampus. In this experimental study adult male Sprague-Dawley rats re- ceived either saline or lysolecithin (LPC) injections to the right hippocampi. Animals re- ceived intraperitoneal (i.p.) injections of FGF2 (5 ng/g) on days 0, 5, 12 and 26 post-LPC. Expressions of myelin basic protein (Mbp) as a marker of myelination, Olig2 as a marker of OPC proliferation, Nestin as a marker of neural progenitor cells, and glial fibrillary acidic protein (Gfap) as a marker of reactive astrocytes were investigated in the right hippocampi by reverse transcriptase-polymerase chain reaction (RT-PCR). There was reduced Mbp expression at seven days after LPC injection, in- creased expressions of Olig2 and Nestin, and the level of Gfap did not change. FGF2 treatment reversed the expression level of Mbp to the control, significantly enhanced the levels of Olig2 and Nestin, but did not change the level of Gfap. At day-28 post- LPC, the expression level of Mbp was higher than the control in LPC-treated animals that received FGF2. The levels of Olig2, Nestin and Gfap were at the control level in the non-treated LPC group but significantly higher in the FGF2-treated LPC group. FGF2 enhanced hippocampal myelination and potentiated the recruitment of OPCs and neural stem cells (NSCs) to the lesion area. Long-term application of FGF2 might also enhance astrogliosis in the lesion site.

Risk factors affecting human traumatic tympanic membrane perforation regeneration therapy using fibroblast growth factor-2

Objective: The use of growth factors to achieve closure of human traumatic tympanic membrane perforations (TMPs) has recently been demonstrated. However, pretreatment factors affecting healing outcomes have seldom been discussed. The objective of this study was to evaluate pretreatment factors contributing to the success or failure of healing of TMPs using fibroblast growth factor-2 (FGF-2). Design and participants: A retrospective cohort study of 99 patients (43 males, 56 females) with traumatic TMPs who were observed for at least 6 months after FGF-2 treatment between March 2011 and December 2012. Eleven factors considered likely to affect the outcome of perforation closure were evaluated statistically using univariate and multivariate logistic regression analysis. Interventions: Each traumatic TMP was treated by direct application of FGF-2. Main outcome measures: Complete closure versus failure to close. Results: In total, 99 patients were analyzed. The total closure rate was 92/99 (92.9%) at 6 months; the mean closure time was 10.59 ± 6.81 days. The closure rate did not significantly differ between perforations with or without inverted edges (100.0% vs. 91.4%, p = 0.087), among different size groups (p = 0.768), or among different periods of exposure to injury (p = 0.051). However, the closure rate was significantly different between the high- and low-dose FGF-2 groups (85.0% vs. 98.3%, p = 0.010) and between perforations where the umbo or malleus was or was not involved in perforation (85.4% vs. 98.3%, p = 0.012). Additionally, univariate logistic regression analysis tests showed that it was difficult to achieve healing of these perforations with a history of chronic otitis media or residual TM calcification (p = 0.006), the umbo or malleus was involved in perforation (p = 0.038), and with a high dose of FGF-2 (p = 0.035) compared with control groups. Multivariate logistic regression analysis showed that only a history of chronic otitis media and residual TM calcification and perforation close to the umbo or malleus were associated with non-healing of the TM perforation (p = 0.03 and p = 0.017, respectively) with relative risk factors. Conclusions: Direct application of FGF-2 can be used in all traumatic TMPs, the size of the perforation and inverted edges did not affect the closure rate, and the most beneficial dose was sufficient to keep the residual eardrum environment moist, but without adding liquid. Additionally, multivariate logistic regression analysis revealed that a large perforation was not a major risk factor for nonhealing of TM perforations. However, a history of chronic otitis media, residual TM calcification and involvement of the umbo or malleus in perforation were significant risk factors.

Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.

Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.

Evaluation of the optimum time for direct application of fibroblast growth factor to human traumatic tympanic membrane perforations

Objective: The aim of this study was to determine the optimum time for direct application of basic fibroblast growth factor (bFGF) on large traumatic tympanic membrane perforations (TMPs). Study design: Prospective clinical study. Setting: Tertiary University Hospital. Methods: Ninety-three patients, with traumatic TMPs greater in extent than 25% of the entire tympanic membrane, were randomized into observation and bFGF-treated groups (∼0.2–0.25 mL of bFGF solution was applied directly onto the TM once daily and continued until the perforation closed). Initial visit times were subcategorized into perforation durations of ≤3 and >3 days, thereby rendering two subgroups, as follows: A and B in the observation group; and C and D in the bFGF-treated group. The closure rate and mean closure time were evaluated after 6 months. Results: Eighty-six patients were finally analyzed. After 6 months, the bFGF-treated group exhibited a significantly higher total closure rate (97.8 versus 82.5%, p < 0.05) and a shorter mean closure time (12.5 ± 3.4 versus 34.0 ± 5.9 days, p < 0.05) compared with the spontaneous healing group. In addition, in the observation group, visiting time was not associated with differences in closure rate (p > 0.05) and mean closure time (p > 0.05), between the A and B subgroups. Similarly, in the bFGF-treated group, visiting time was not associated with differences in closure rate (p > 0.05) between the C and D subgroups. However, the D subgroup was characterized by significantly shortened mean closure time compared with the C subgroup (p < 0.05). Conclusions: This study shows the beneficial effect of bFGF on human traumatic large TMPs when applied after the 3rd day post-injury had passed (i.e. during the proliferative stage of wound healing). The procedure can not only significantly shorten closure time but can also reduce both the clinical administration duration and occurrence of side-effects associated with bFGF.

The role of FGF2 in spinal cord trauma and regeneration research

The role of <scp>FGF</scp>2 in spinal cord trauma and regeneration research

Cooperative Effects of FGF-2 and VEGF-A in Periodontal Ligament Cells

We previously demonstrated that topical application of fibroblast growth factor (FGF)-2 enhanced periodontal tissue regeneration. Although angiogenesis is a crucial event for tissue regeneration, the mechanism(s) by which topically applied FGF-2 induces angiogenesis in periodontal tissues has not been fully clarified. In this study, we investigated whether FGF-2 could induce vascular endothelial growth factor (VEGF)-A expression in periodontal ligament (PDL) cells and whether cell-to-cell interactions between PDL cells and endothelial cells could stimulate angiogenesis. FGF-2 induced VEGF-A secretion from MPDL22 cells (mouse periodontal ligament cell line) in a dose-dependent manner. Transwell and wound-healing assays revealed that co-stimulation with FGF-2 plus VEGF-A synergistically stimulated the migration of MPDL22 cells. Interestingly, co-culture of MPDL22 cells with bEnd5 cells (mouse endothelial cell line) also stimulated VEGF-A production from MPDL22 cells and tube formation by bEnd5 cells. Furthermore, time-lapse analysis revealed that MPDL22 cells migrated close to the tube-forming bEnd5 cells, mimicking pericytes. Thus, FGF-2 induces VEGF-A expression in PDL cells and induces angiogenesis in combination with VEGF-A. Cell-to-cell interactions with PDL cells also facilitate angiogenesis.

Healing outcomes of large (&gt;50%) traumatic membrane perforations with inverted edges following no intervention, edge approximation and fibroblast growth factor application; a sequential allocation, three‐armed trial

ObjectiveThe goal of this study was to evaluate the effects of perforation edge approximation and direct application of basic fibroblast growth factor (bFGF) each alone on the healing of large traumatic tympanic membrane perforations with inverted edges in humans.Study DesignProspective, sequential allocation, three-armed, controlled clinical study.SettingUniversity-affiliated teaching hospital.ParticipantsFifty-eight patients with large traumatic tympanic membrane perforations (i.e. affecting >50% of the surface area) with inverted edges were recruited. They were sequentially allocated to three groups: no intervention (n & 18), edge approximation alone (n & 20) and direct application of bFGF (n & 20). Otoscopy were performed before the treatment and at follow-up visits.Main outcome measuresThe closure rate, closure time and rate of otorrhoea.ResultsApplication of bFGF yielded a significantly higher average rate of perforation closure (100%) than edge approximation (60%) and no intervention (56%) (P < 0.05). It also significantly shortened the average closure time (12.4 ± 3.6 days) as compared to edge approximation (46.3 ± 8.7 days) and no intervention control (48.2 ± 5.3 days) (P < 0.05). Purulent otorrhoea was observed in none of the three groups.ConclusionEdge approximation of inverted edges has little benefit in improving the healing outcome of large traumatic tympanic membrane perforations and thus is not an ideal treatment option for large traumatic tympanic membrane perforations. Application of bFGF materially improves the closure rate of large traumatic tympanic membrane perforations and significantly shortens the closure time.

Fibroblast Growth Factor-2, Bone Homeostasis and Fracture Repair

There remains a great need to develop therapeutic agents to treat critical size defects and non-union fractures and one of the potential agents is recombinant human fibroblast growth factor 2 (FGF-2). We discuss the function of FGF-2 in bone formation, bone resorption, and downstream signaling pathways and review the role of exogenous FGF-2 in fracture healing. The importance of endogenous FGF-2 in bone formation and its potential importance in fracture healing in response to parathyroid hormone (PTH) and bone morphogenetic protein 2 (BMP2) is described. In addition we will review, FGF-2 signaling crosstalk with Wnt signaling and PTH signaling in bone formation and repair. Finally, we discuss the outstanding unresolved issues in the application of FGF-2 as therapeutic agent for bone regeneration.

Changes in fibroblast growth factor-2 and FGF receptors in the frog visual system during optic nerve regeneration

We have previously shown that application of fibroblast growth factor-2 (FGF-2) to cut optic nerve axons enhances retinal ganglion cell (RGC) survival in the adult frog visual system. These actions are mediated via activation of its high affinity receptor FGFR1, enhanced BDNF and TrkB expression, increased CREB phosphorylation, and by promoting MAPK and PKA signaling pathways. The role of endogenous FGF-2 in this system is less well understood. In this study, we determine the distribution of FGF-2 and its receptors in normal animals and in animals at different times after optic nerve cut. Immunohistochemistry and Western blot analysis were conducted using specific antibodies against FGF-2 and its receptors in control retinas and optic tecta, and after one, three, and six weeks post nerve injury. FGF-2 was transiently increased in the retina while it was reduced in the optic tectum just one week after optic nerve transection. Axotomy induced a prolonged upregulation of FGFR1 and FGFR3 in both retina and tectum. FGFR4 levels decreased in the retina shortly after axotomy, whereas a significant increase was detected in the optic tectum. FGFR2 distribution was not affected by the optic nerve lesion. Changes in the presence of these proteins after axotomy suggest a potential role during regeneration.

Periodontal regeneration using an injectable bone cement combined with BMP-2 or FGF-2

Periodontitis is a frequently diagnosed oral disease characterized by bone resorption and soft tissue loss around teeth. Unfortunately, currently available therapies only slow or arrest progress of the disease. Ideally, treatment of periodontal defects should be focused on complete regeneration of the lost tissues [(bone and periodontal ligament (PDL)]. As a result, this study used intrabony defects to evaluate the regenerative potential of an injectable macroporous calcium phosphate cement (CaP) in combination with bone morphogenetic protein-2 (BMP-2) or fibroblast growth factor-2 (FGF-2). After creating 30 periodontal defects in 15 Wistar rats, three treatment strategies were conducted: application of CaP only, CaP + BMP-2 and CaP + FGF-2. Animals were euthanized after 12 weeks and processed for histology and histomorphometry. Using CaP alone resulted in limited effects on PDL and bone healing. CaP + BMP-2 showed a good response for bone healing; a significant 2.4 fold increase in bone healing score was observed compared to CaP. However, for PDL healing, CaP + BMP-2 treatment showed no difference compared to the CaP group. The best results were observed with the combined treatment of CaP + FGF-2, which showed a significant 3.3 fold increase in PDL healing score compared to CaP + BMP-2 and a significant 2.6 fold increase compared to CaP. For bone healing, CaP + FGF-2 showed a significant 1.9 fold increase compared to CaP but no significant difference was noted compared to the CaP + BMP-2 group. The combination of a topical application of FGF-2 and an injectable CaP seems to be a promising treatment modality for periodontal regeneration.

FGF-2 Stimulates Periodontal Regeneration

The efficacy of the local application of recombinant human fibroblast growth factor-2 (FGF-2) in periodontal regeneration has been investigated. In this study, a randomized, double-blind, placebo-controlled clinical trial was conducted in 253 adult patients with periodontitis. Modified Widman periodontal surgery was performed, during which 200 µL of the investigational formulation containing 0% (vehicle alone), 0.2%, 0.3%, or 0.4% FGF-2 was administered to 2- or 3-walled vertical bone defects. Each dose of FGF-2 showed significant superiority over vehicle alone (p < 0.01) for the percentage of bone fill at 36 wks after administration, and the percentage peaked in the 0.3% FGF-2 group. No significant differences among groups were observed in clinical attachment regained, scoring approximately 2 mm. No clinical safety problems, including an abnormal increase in alveolar bone or ankylosis, were identified. These results strongly suggest that topical application of FGF-2 can be efficacious in the regeneration of human periodontal tissue that has been destroyed by periodontitis.

Diverse FGF receptor signaling controls astrocyte specification and proliferation

During CNS development, pluripotency neuronal progenitor cells give rise in succession to neurons and glia. Fibroblast growth factor-2 (FGF-2), a major signal that maintains neural progenitors in the undifferentiated state, is also thought to influence the transition from neurogenesis to gliogenesis. Here we present evidence that FGF receptors and underlying signaling pathways transmit the FGF-2 signals that regulate astrocyte specification aside from its mitogenic activity. Application of FGF-2 to cortical progenitors suppressed neurogenesis whereas treatment with an FGFR antagonist in vitro promoted neurogenesis. Introduction of chimeric FGFRs with mutated tyrosine residues into cortical progenitors and drug treatments to specifically block individual downstream signaling pathways revealed that the overall activity of FGFR rather than individual autophosphorylation sites is important for delivering signals for glial specification. In contrast, a signal for cell proliferation by FGFR was mainly delivered by MAPK pathway. Together our findings indicate that FGFR activity promotes astrocyte specification in the developing CNS.

Establishment of an animal model of a pasteurized bone graft, with a preliminary analysis of muscle coverage or FGF-2 administration to the graft

BackgroundPasteurized bone grafting is used following the excision of a bone tumor for the purpose of eliminating neoplastic cells while preserving bone-inducing ability. In the hopes of guaranteeing the most favourable results, the establishment of an animal model has been urgently awaited. In the course of establishing such a model, we made a preliminary examination of the effect of muscle coverage or fibroblast growth factor 2 (FGF-2) administration radiographically.MethodsForty pasteurized intercalary bone grafts of the Wistar rat femur treated at 60°C for 30 min were reimplanted and stabilized with an intramedullary nail (1.1 mm in diameter). Some grafts were not covered by muscle after the implantation, so that they could act as a clinical model for wide resection, and/or these were soaked with FGF-2 solution prior to implantation. The grafts were then divided into 3 groups, comprising 12 grafts with muscle-covering but without FGF-2 (MC+; FGF2-), 12 grafts without muscle-covering and without FGF-2 (MC-; FGF2-) and 16 grafts without muscle covering but with FGF-2 (MC-; FGF2+).ResultsAt 2 weeks after grafting, the pasteurized bone model seemed to be successful in terms of eliminating living cells, including osteocytes. At 4 weeks after grafting, partial bone incorporation was observed in half the (MC+; FGF2-) cases and in half the (MC-; FGF2+) cases, but not in any of the (MC-; FGF2-) cases. At 12 weeks after grafting, bone incorporation was seen in 3 out of 4 in the (MC+; FGF2-) group (3/4: 75%) and in 3 out of 8 in the (MC-; FGF2+) group (3/8: 38%). However, most of the grafted bones without FGF-2 were absorbed in all the cases, massively, regardless of whether there had been muscle-covering (MC+; FGF2-; 4/4: 100%) or no muscle-covering (MC-; FGF2-; 4/4: 100%), while bone absorption was noted at a lower frequency (2/8: 25%) and to a lower degree in the (MC-; FGF2+) group.ConclusionIn conclusion, we have established an animal pasteurized bone graft model in rats. Pasteurized bone was able to maintain bone induction ability. Despite the low number of cases in each group, the results of each group suggest that muscle-covering has an effect on bone incorporation, but that it is not able to prevent bone absorption to the pasteurized bone. However, an application of FGF-2 may have a positive effect on bone incorporation and may be able to prevent bone absorption of the graft in cases of pasteurized bone graft.

The effect of a local application of fibroblast growth factor-2 on tendon-to-bone remodeling in rats with acute injury and repair of the supraspinatus tendon

We investigated the effect of application of fibroblast growth factor (FGF)-2 on the tendon-to-bone remodeling of repaired supraspinatus tendon in rats subjected to bilateral detachment. FGF-2 (100 mg/kg) in a fibrin sealant or sealant alone was applied on the right and left shoulders, respectively. Twelve animals each at 2, 4, and 6 weeks after surgery were sacrificed for histological analysis (n = 5) and biomechanical Q1 testing (n = 7). Histologically, at 2 weeks, FGF-treated specimens had significantly higher tendon-to-bone insertion maturing scores then untreated specimens (P < .002). At 4 and 6 weeks, the scores of FGF-treated and untreated specimens were similar (P > .05). Biomechanically, FGF-treated specimens were stronger at 2 weeks (P = .001); at 4 and 6 weeks, both specimens exhibited similar strength (P > .05). The initial tendon-to-bone remodeling was accelerated by a local application of FGF-2. This may represent a clinically important improvement in rotator cuff repair.