Abstract
Cyclosporin A (CyA) induces gingival overgrowth via its stimulatory effects on expression of transforming growth factor-beta1 (TGF-beta1) and collagen. It is not known whether CyA has a direct effect on gingival fibroblasts or induces its effect indirectly via stimulation of myofibroblast transdifferentiation. The present study was undertaken to examine the in vivo and in vitro effect of CyA on myofibroblast transdifferentiation. Rats were treated for 60 days with a daily subcutaneous injection of CyA, and the gingival overgrowth tissue was analyzed by immunohistochemistry. In vitro, fibroblasts from normal gingiva (NG) were cultured in the presence of different concentrations of CyA, and subjected to semi-quantitative reverse transcriptase-polymerase chain reaction and western blot. Although CyA treatment stimulated TGF-beta1 expression by NG fibroblasts, it lacked to induce expression and production of isoform alpha of smooth muscle actin (alpha-SMA), the specific myofibroblast marker. The expression levels of connective tissue growth factor (CTGF), which has been considered a key molecule to promote the transdifferentiation of myofibroblasts via TGF-beta1 activation, were unaffected by CyA. Our results demonstrate that CyA-induced gingival overgrowth is not associated with activation of myofibroblast transdifferentiation, since CyA is not capable to increase CTGF expression.
Highlights
Cyclosporin A (CyA) is a cyclic endecapeptide with potent immunosuppressive properties, which has made it the drug of choice in many transplantation procedures.[1,2] Following the clinical use of CyA, a number of adverse effects were recorded
We demonstrated that TGF-β1 promotes a dose- and timedependent increase in the expression of α of smooth muscle actin (α-SMA), whereas interferon γ (IFNγ) blocks it and prevents the fibroblast-myofibroblast switch induced by TGFβ1 on normal gingiva (NG) cultures via stimulation of Smad 7 and, subsequently, inhibition of connective tissue growth factor (CTGF).[11]
Since gingival overgrowth induced by CyA provides an excellent model for the study of connective tissue fibrosis, CyA-treated NG fibroblasts produce abundant extracellular matrix and high levels of TGF-β1, and myofibroblasts represent a hallmark of interstitial fibrosis, the purpose of this study was to analyze the expression of α-SMA, TGF-β1 and CTGF in CyA-induced gingival overgrowth
Summary
Cyclosporin A (CyA) is a cyclic endecapeptide with potent immunosuppressive properties, which has made it the drug of choice in many transplantation procedures.[1,2] Following the clinical use of CyA, a number of adverse effects were recorded. One of these was gingival overgrowth that was first reported by Calne et al.[2] (1979), the term “CyAinduced gingival enlargement” was mentioned for the first time in dental literature by Rateitschak-Plus et al.[3] (1983). CyA induces transforming growth factor-beta[1] (TGF-β1) expression by human gingival fibroblasts,[5,6] which is, in association with an elevated synthesis of collagen, an intrinsic characteristic of myofibroblasts.[7]
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