Abstract
Background: Gingival hyperplasia could occur after the administration of cyclosporine A. Up to 90% of the patients submitted to immunosuppressant drugs have been reported to suffer from this side effect. The role of fibroblasts in gingival hyperplasia has been widely discussed by literature, showing contrasting results. In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the gene expression profile of human fibroblasts after cyclosporine A administration. Materials and methods: Primary gingival fibroblasts were stimulated with 1000 ng/mL cyclosporine A solution for 16 h. Gene expression levels of 57 genes belonging to the “Extracellular Matrix and Adhesion Molecules” pathway were analyzed using real-time PCR in treated cells, compared to untreated cells used as control. Results: Expression levels of different genes were significantly de-regulated. The gene CDH1, which codes for the cell adhesion protein E-cadherin, showed up-regulation. Almost all the extracellular matrix metalloproteases showed down-regulation (MMP8, MMP11, MMP15, MMP16, MMP24, MMP26). The administration of cyclosporine A was followed by down-regulation of other genes: COL7A1, the transmembrane receptors ITGB2 and ITGB4, and the basement membrane constituents LAMA2 and LAMB1. Conclusion: Data collected demonstrate that cyclosporine inhibits the secretion of matrix proteases, contributing to the accumulation of extracellular matrix components in the gingival connective tissue, causing gingival overgrowth. Patients affected by gingival overgrowth caused by cyclosporine A need to be further investigated in order to determine the role of this drug on fibroblasts.
Highlights
Gingival hyperplasia could occur after the administration of cyclosporine A
In order to demonstrate the effect of cyclosporine A on the extracellular matrix component of fibroblasts, we investigated the expression of 57 genes that code for “Extracellular Matrix and Adhesion Molecules” of gingival fibroblasts
The E-cadherin levels measured by enzyme linked immunoassay (ELISA) after cyclosporine treatment showed an expected increase of E-cadherin levels (4.5-fold ± 0.3) in treated fibroblasts vs. untreated control (Figure 1), confirming the gene expression results obtained in real-time PCR
Summary
Gingival hyperplasia could occur after the administration of cyclosporine A. The incidence of overgrowth of gingiva induced by cyclosporine A (OGIC) is in the range of 20–80% of patients [3]; in addition, up to 90% of transplant recipient patients, who have been submitted to cyclosporine A therapy, present OGIC [4] Several factors such as age, sex, duration of treatment, and dosage of the prescribed cyclosporine A influence the severity of clinical manifestation of OGIC [5,6,7]. To prevent OGIC several approaches have been proposed, such as drug substitution or cyclosporine A dose reduction, as well as oral hygiene programs and surgical interventions, but each of these approaches may have contraindications. Surgical intervention is only proposed for cosmetic cases, whilst oral hygiene protocols have been demonstrated efficacy in controlling OGIC, but could not inhibit its development
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