Effect of cyclosporin A on human gingival fibroblast collagen turnover in relation to the development of gingival overgrowth: an in vitro study.
In a significant number of cases (25-81%) immunosuppressant treatment with cyclosporin A (CsA) is associated with gingival overgrowth, seriously interfering with the functions of mastication and speech. In CsA-induced gingival enlargement, quantitative modifications of the extracellular matrix components occur, and collagen (COL) metabolism and matrix metalloproteinases (MMPs) have been suggested as being the main targets. Since the mechanisms at the basis of CsA-induced gingival overgrowth are not yet completely understood, our aim was to analyze the effect of CsA on COL turnover in cultured human gingival fibroblasts. Cultured human gingival fibroblasts from four healthy volunteers were incubated with CsA (800 ng/ml) or with its vehicle (VH) for variable intervals of time (24, 48, 72 h). Fibroblast morphology was studied by light and electron microscope. Collagen type I (COL-I), MMP-1, MMP-2, TIMP-1 and TGF-beta1 mRNA were determined by RT-PCR; COL-I and MMP-1 by dot blot, and MMP-2 by zymography. Our results evidenced an up-regulation of COL-I and TGF-beta1 gene expression 72 h after CsA treatment. MMP-1, MMP-2 and TIMP-1 mRNA levels are affected but not significantly. Protein analysis revealed COL-I increase at all the considered times and, 72 h after CsA treatment, reduced collagenolytic levels. Our data suggest that COL accumulation during CsA-induced gingival overgrowth may be mainly sustained by an altered COL-I degradation due to decreased MMP-1 activity. However, interindividual differences of collagenase levels after CsA treatment suggest that a genetic predisposition to develop gingival overgrowth may be relevant.
Gagliano
Nicoletta
N
Department of Human Morphology-LITA, University of Milan, Via Fratelli Cervi 93, 20090 Segrate, Milan, Italy. nicoletta.gagliano@unimi.it
Moscheni
Claudia
C
Dellavia
Claudia
C
Torri
Carlo
C
Stabellini
Giordano
G
Ferrario
Virgilio F
VF
Gioia
Magda
M
D002478:Cells, Cultured; D024042:Collagen Type I / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019214:Gingival Overgrowth / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008854:Microscopy, Electron; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D007166:Immunosuppressive Agents; C508960:TGFB1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1