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Background: Transforming growth factor-β1 (TGF-β1), its downstream signaling mediators (Smad proteins), and specific targets, including connective tissue growth factor (CTGF), play important roles in tissue remodeling and fibrosis via myofibroblast activation. We investigated the effect of overexpression of Smad7, a TGF-β1 signaling inhibitor, on transition of gingival fibroblast to myofibroblast. Moreover, we analyzed the participation of CTGF on TGF-β1-mediated myofibroblast transformation. Methods: To study the inhibitory effect of Smad7 on TGF-β1/CTGF-mediating gingival fibroblast transition into myofibroblasts, we stably overexpressed Smad7 in normal gingival fibroblasts and in myofibroblasts from hereditary gingival fibromatosis (HGF). Myofibroblasts were characterized by the expression of the specific marker isoform α of the smooth muscle actin (α-SMA) by Western blot, flow cytometry, and immunofluorescence. Enzyme-linked immunosorbent assay for type I collagen was performed to measure myofibroblast activity. CTGF's role on myofibroblast transformation was examined by enzyme-linked immunosorbent assay and small interference RNA. Results: TGF-β1 induced the expression of α-SMA and CTGF, and small interference RNA-mediating CTGF silencing prevented fibroblast-myofibroblast switch induced by TGF-β1. In Smad7-overexpressing fibroblasts, ablation of TGF-β1-induced Smad2 phosphorylation marked decreased α-SMA, CTGF, and type I collagen expression. Similarly, HGF transfectants overexpressing Smad7 demonstrated low levels of α-SMA and phospho-Smad2 and significant reduction on CTGF and type I collagen production. Conclusions: CTGF is critical for TGF-β1-induced gingival fibroblast-myofibroblast transition, and Smad7 overexpression is effective in the blockage of myofibroblast transformation and activation, suggesting that treatments targeting myofibroblasts by Smad7 overexpression may be clinically effective in gingival fibrotic diseases, such as HGF. [ABSTRACT FROM AUTHOR]

Background: Gingival fibromatosis is a rare condition characterized by a generalized enlargement of the buccal and lingual aspects of the attached and marginal gingiva. Methods: This case report describes the periodontal management of a 13-year-old female patient with gingival fibromatosis associated with Zimmermann-Laband syndrome. The patient presented with gingival enlargement involving the maxillary and the mandibular arches, anterior open bite, and non-erupted teeth. Periodontal treatment included gingivectomy in all four quadrants. Results: Histopathologic evaluation of the excised tissue supported the diagnosis of gingival fibromatosis. A significant improvement in esthetic appearance and eruption of the non-erupted teeth were obtained. The patient was referred for appropriate orthodontic treatment and has been closely followed for the earliest signs of recurrence of gingival enlargement. Conclusions: The successful therapy for gingival fibromatosis depends on correctly identifying the etiological factors and improving the impaired function and esthetic appearance through surgical intervention and adjunctive orthodontics. Maintaining treatment results depends on preservation of periodontal health. [ABSTRACT FROM AUTHOR]

Background: Fatty acid synthase (FAS) is the enzyme that synthesizes palmitate from malonyl-CoA and acetyl-CoA. Recent studies have shown that FAS is overexpressed in human cancers and that its activity is necessary for cell proliferation. Hereditary gingival fibromatosis (HGF) is a genetic disease manifested as a progressive enlargement of the gingiva. The pathogenesis of this condition is not understood; however, a proliferative advantage of HGF fibroblasts in comparison with ceils from nor real gingiva (NG) has been described. The aim of this study was to investigate the role of FA8 in NG and HGF fibroblast proliferation. Methods: NG and HGF fibroblasts had their proliferative potential assessed by automated cell counting and immunocytochemistry against Ki-67 or proliferating cell nuclear antigen (PCNA). The production of FAS, androgen receptor (AR), and ErbB2 was analyzed by Western blot and the pattern of FAS expression studied by immunocytochemistry. FAS activity was blocked by the specific inhibitor cerulenin. Results: Higher proliferation rates were found in fibroblasts isolated from HGF than from NG. HGF fibroblasts with greater proliferative potential produced more FAS and AR than the cell lines with lower growth rates, and all studied cell lines produced similar amounts of the ErbB2 protein. In addition, the FAS inhibitor cerulenin was able to significantly reduce the proliferation of both NG and HGF cells. Conclusions: These results show that FAS is expressed by gingival fibroblasts and that highly proliferative HGF cells produced more FAS and AR than the other fibroblast cell lines. Moreover, FAS inhibition significantly reduced both NG and HGF fibroblast growth, suggesting a role for the androgen-driven fatty acid biosynthesis in their proliferation. [ABSTRACT FROM AUTHOR]

Background: Hereditary gingival fibromatosis (HGF) is a fibrotic gingival enlargement. In previous work, HGF fibroblasts grew faster and produced more collagen and fibronectin (FN) than normal gingival (GN) fibroblasts. HGF FN and collagen production, but not proliferation, were under autocrine transforming growth factor (TGF)-β control, suggesting other means of activation of HGF proliferation. Elevated/pro longed expression of the protooncogene c-myc is implicated in disregulation of cell growth. The objectives of this study were to: 1) determine if c-myc expression is abnormal in quiescent and serum-stimulated HGF and GN fibroblasts and 2) determine the relationship between c-myc expression and fibroblast proliferation using a c-myc antisense oligonucleotide (ODN). Methods: Proliferation was determined by enzyme-linked immunosorbent assay (ELISA), measuring incorporation of bromodeoxyuridine into DNA. Expression of c-myc was determined by quantitative polymerase chain reaction (PCR), using incorporation of fluorescent dCTP and detection via electrophoresis. Results: Proliferation was minimal until 24 hours or more after serum stimulation, when HGF proliferation was greater than GN (P ≤0.02). All cells expressed c-myc mRNA at quiescence and ≥1 hour alter serum stimulation. Expression of c-myc in quiescent HGF fibroblasts was elevated, and it peaked and remained higher after serum stimulation than in GN cells. Proliferation of an HGF cell line was inhibited by 4 µM c-myc antisense ODN (14% decrease; P ≤0.006) and 8 µM c-myc antisense ODN (-80% decrease: P ≤0.0001), but generally not by c-myc sense ODN. This effect was reversed by hybridizing the c-myc antisense and sense ODNs (P = 0.007). Conclusion: Data suggest that elevated proliferation of an HGF fibroblast cell line is related to elevated c-myc expression. [ABSTRACT FROM AUTHOR]

Background: Zimmermann-Laband syndrome b a rare autosomal dominant disorder that is characterized by gingival fibromatosis, ear, nose, bone, and nail defects, and hepatosplenomegaly. Methods: This case report describes the clinical presentation and periodontal findings in a 13-year-old female patient with previously undiagnosed Zimmermann-Laband syndrome. Results: Clinical and radiographic findings and genetic counseling confirmed the diagnosis of Zimmermann-Laband syndrome. The most striking oral findings mere the presence of gingival enlargement involving both the maxillary and mandibular arches, anterior open bite, non-erupted teeth, and two supernumerary teeth. Periodontal treatment consisted of gingivectomy in four quadrants. Histopathologic evaluation of excised tissue supported the diagnosis of gingival fibromatosis. The patient was referred for appropriate orthodontic treatment and genetic counseling, and has been closely followed for the earliest signs of hepatosplenomegaly. Conclusions: Dental practitioners should be alert for developmental abnormalities that may occur in patients with gingival fibromatosis as this may indicate the presence of a rare disorder tike Zimmermann-Laband syndrome. A comprehensive medical history and physical systemic evaluation are essential for correct diagnosis and treatment of these cases. [ABSTRACT FROM AUTHOR]

Background: Increased collagen and extracellular matrix deposition within the gingiva is the main characteristic feature of hereditary gingival fibromatosis (HGF). To date, it is not well established if these events are a consequence of alterations in the collagen and other extracellular matrix molecules synthesis or disturbances in the homeostatic equilibrium between synthesis and degradation of extracellular matrix molecules. Cytokines are important regulators of expression of the profibrogenic genes, including type I collagen and its molecular chaperone heat shock protein (Hsp)47 and proteolytic enzymes degrading extracellular matrix such as matrix metalloproteinases-1 and -2 (MMP-1 and MMP-2}. Methods: In this study, we analyzed the expression and production of type I collagen, Hsp47, MMP-1, and MMP-2 in normal gingiva (NG) and HGF fibroblasts, and investigated the effects of transforming growth factor-beta1 (TGF-β1), interleukin-6 (1L-6) and interferon-gamma (IFN-γ) on the expression of these genes by NG and HGF fibroblasts. Results: Our results obtained from semi-quantitative reverse transcription-polymerase chain reactions (RT-PCR), Western blots, enzyme-linked immunosorbent assays (ELISA), and enzymographies clearly demonstrated that the expression and production of type I collagen and Hsp47 were significantly higher in fibroblasts from HGF than from NG, whereas MMP-1 and MMP-2 expression and production were lower in fibroblasts from HGF patients. Addition of TGF-β1 and IL-6, which are produced in greater amounts by HGF fibroblasts, promoted an increase in type I collagen and Hsp47 and a decrease in MMP-1 and MMP-2 expression. IFN-γ reduced both type I collagen and Hsp47 expression, whereas it had a slight effect on the expression of MMP-1 and MMP-2. Conclusion: These patterns of expression and production suggest that enhanced TGF-β1 and IL-6 production simultaneously increase the synthesis and reduce the proteolytic activities of fibroblasts from patients with HGF, which may favor the accumulation of extracellular matrix observed in patients with this condition. [ABSTRACT FROM AUTHOR]

Background: Hereditary gingival fibromatosis (HGF) is a rare oral disease characterized by a slow and progressive enlargement of both the maxilla and mandible gingiva. Increased proliferation, elevated synthesis of extracellular matrix, particularly collagen, and reduced levels of matrix metalloproteinases seem to contribute to the pathogenesis of gingival overgrowth in HGF patients. Transforming growth factor-β1 (TGF-β1) is an important cytokine thought to play a major role in fibrotic disorders such as HGF due to its ability to stimulate the synthesis and reduce the degradation of extracellular matrix. In HGF fibroblasts, TGF-β1 autocrine stimulation reduces expression and production of matrix metalloproteinases. However, the role of TGF-β1 in fibroblast growth modulation has not been established in this disease. Methods: The aim of this study was to confirm the increased proliferation rate of HGF fibroblast cell lines and to explore a possible autocrine role of TGF-β1 as a cell growth stimulator by blocking production of this endogenous cytokine using 2 well-established systems: antisense oligonucleotides and neutralizing antibodies. Results: Four different cellular proliferation assays, bromodeoxyuridine labeling, argyrophilic nucleolar organizing region staining, proliferating cell nuclear antigen, and mitotic indexes, confirmed that fibroblasts from HGF proliferate significantly faster than those from normal gingiva. Antisense oligonucleotides reduced TGF-β1 production as demonstrated by capture enzyme-linked immunosorbent assay, whereas TGF-β1 expression levels were not significantly modified. Blocking TGF-β1 synthesis with oligonucleotides or its activity with specific antibodies resulted in a decreased magnitude of HGF fibroblast proliferation. Conclusion: These results are consistent with the existence of an autocrine role of TGF-β1 as a stimulator of HGF fibroblast proliferation. [ABSTRACT FROM AUTHOR]

HEREDITARY GINGIVAL FIBROMATOSIS (HGF) is a fibrotic enlargement of the gingival. HGF gingiva contains large amounts of collagen and other extracellular matrix (ECM) molecules. In vitro, HGF fibroblast produce greater amounts of the ECM components fibronection (FN) and type 1 collagen than normal human gingival (GN) fibroblasts. Transforming growth factor β (TGF β) is a cytokine important in regulating tissue repair and regeneration after injury, and stimulating fibroblast proliferation and the production of FN and collagens. The objective of this study was to determine whether HGF fibroblasts produce TGF β and, with the use of neutralizing antibodies to TGF β isoforms, if their increased expression of FN and type 1 collagen is under autocrine TGF β control. The HGF strains produced greater amounts of TGF β1 and TGF β2 (p ≤ 0.003) as well as FN (P ≤ 0.04) and type I collagen (P ≤ 0.03) (measured by specific ELISA) than the GN strains. Treatment of HGF fibroblasts with anti-TGF β1, β2, or β3, as well as a combination of all 3 antibodies, decreased their FN production by up to 60% (P ≤ 0.04), and was able to decrease FN production by HGF fibroblasts to the levels of the GN fibroblasts. When used alone, the neutralizing antibodies decreased type I collagen production by the HGF fibroblasts by up to 40% (P = 0.014), and treatment with all 3 antibodies caused decreases of up to 55% (P = 0.0005). The results suggest that autocrine stimulation by the increased amounts of TGF β isoforms made by HGF fibroblasts contributes to their increased production of FN and type 1 collagen. [ABSTRACT FROM AUTHOR]