Role of transforming growth factor β-connective tissue growth factor pathway in dihydropyridine calcium channel blockers-induced gingival overgrowth

Background: Gingival overgrowth was reported as a side effect after chronic administration of several drugs, which, despite their different pharmacological effect, seem to have the gingival mucosa as a secondary target. The thickness of the gingival epithelium and fibrosis in the lamina propria are unspecific changes that together determine the enlargement of the gingival mucosa, but the molecular mechanisms responsible for the imbalance of collagen synthesis/breakdown are still uncertain. The aim of our study was to assess the role of TGF-beta 1-CTGF pathway in the activation of cells with a fibrilogenetic phenotype responsible for the gingival fibrosis developed after chronic administration of dihydropyridine calcium channel blockers. Materials and Methods: Fragments of gingival tissue collected from patients clinically diagnosed with gingival overgrowth after chronic administration of nifedipine and amlodipine were processed for paraffin embedding. Serial sections were used for routine staining Masson and Gomori's silver impregnation in order to reveal collagen accumulation and for immunohistochemical reactions to label TGF-beta 1, CTGF, Ki67 and alpha-SMA. Results: Routine histological staining for collagen revealed the presence of gingival fibrosis and a change between type I collagen/type III collagen ratio. Regardless of the drug involved, many slides showed extended TGF-beta 1 positive areas, mainly in the profound - spinous and basal - layers, but also in some cells from the subjacent connective tissue. CTGF exposed intense positive reaction in the basal and parabasal layers, but also in resident cells from the connective tissue. Ki67 immunolabeling did not reveal an increased fibroblast proliferation in the lamina propria. We noticed the presence of a small number of myofibroblasts in the lamina propria. Conclusions: These findings suggest that TGF-beta 1-CTGF axis is activated in dihydropyridine calcium channel blockers-induced gingival overgrowth and exerts a different control on the activation of fibroblasts with a synthetic phenotype. These results also have implications for better understanding mechanisms of fibrosis and the future use of this pathogenic pathway as a therapeutic target in order to limit gingival fibrosis.