Epithelial and connective tissue cell CTGF/CCN2 expression in gingival fibrosis

Abstract

Gingival overgrowth and fibrosis is a side effect of certain medications and occurs in non-drug induced forms either as inherited (human gingival fibromatosis) or idiopathic gingival overgrowth. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Connective tissue growth factor (CTGF/CCN2) expression is positively related to the degree of fibrosis in these tissues. In the present study, the hypothesis was investigated that CTGF/CCN2 is expressed in human gingival fibromatosis tissues and contributes to this form of non-drug-induced gingival overgrowth. Histopathology/immunohistochemistry studies show that human gingival fibromatosis lesions are highly fibrotic, similar to phenytoin-induced lesions. Connective tissue CTGF/CCN2 levels were equivalent to the expression in phenytoin-induced gingival overgrowth. The additional novel observation was made that CTGF/CCN2 is highly expressed in the epithelium of fibrotic gingival tissues. This finding was confirmed by in situ hybridization. Real time PCR analyses of RNA extracted from control and drug-induced gingival overgrowth tissues for CTGF/CCN2 were fully consistent with these findings. Finally, normal primary gingival epithelial cell cultures were analyzed for the basal and TGF-β1 or lysophosphatidic acid stimulated CTGF/CCN2 expression at the protein and RNA levels. Data indicate that fibrotic human gingival tissues express CTGF/CCN2 in both the epithelium and connective tissues and cultured gingival epithelial cells express CTGF/CCN2, and lysophosphatidic acid further stimulates CTGF/CCN2 expression. These findings suggest that interactions between epithelial and connective tissues could contribute to gingival fibrosis.

Molecular and Clinical Aspects of Drug-induced Gingival Overgrowth

“…These studies are most relevant to phenytoin-and possibly nifedipine-induced gingival overgrowth and idiopathic human gingival overgrowth, which are fibrotic, unlike ciclosporin-induced lesions (Uzel et al 2001). CCN2 is strongly and rapidly up-regulated by TGF-β in a variety of cells derived from multiple tissues, including human gingival fibroblasts and epithelial cells (Kantarci et al 2006). Gingival fibroblasts, however, are unusual in that PGE 2 only slightly down-regulates CCN2 levels, in sharp contrast to lung and kidney fibroblasts, in which CCN2 is dramatically downregulated by PGE 2 (Ricupero et al 1999;Black et al 2007).…”

Glutathione S-Transferase Mu2 Suppresses Cancer Cell Metastasis in Non–Small Cell Lung Cancer

“…Regulators such as VEGF, S1P, and hypoxia-inducible factor (HIF)-1a have been reported to induce CCN2 production in different cells (26)(27)(28). CCN2 is also upregulated by other fibrogenetic cytokines including angiotension II, endothelin 1, and thrombin (29)(30)(31).…”

Epithelial to Mesenchymal Transition in Gingival Overgrowth

“…5 Moreover, we have observed elevated expressions of CCN2/ CTGF in both epithelial and connective tissue cells in phenytoin-induced gingival overgrowth tissues. 6 CCN2/CTGF is considered to be a marker of fibroblastic mesenchymal cells and is increased in cells undergoing epithelial to mesenchymal transition (EMT) in development, and in fibrosis. [7][8][9] The observation of elevated CCN2/CTGF levels in the epithelium of phenytoin gingival overgrowth lesions combined with the histopathology of all gingival overgrowth lesions has led us to test the hypothesis that EMT can contribute to human gingival overgrowth and fibrosis.…”