Expression And Significance Of MMP2, CD147, CyPA In CsA Induced Gingival Overgrowth

Background:Cyclosporin A (CsA) is an powerful immunosuppressant drug widely used in organtransplant recipients and people with autoimmune disorders. Its major mode of action isinhibition of the production of cytokines involved in the regulation of T-cell activation.However, the drug presents a long list of side effects: nephrotoxicity, hypercholesterolemia,hypertrichosis, hypertrichosis, hypertension and so on. The most common oral side effectof CsA is the gingival overgrowth. So, it is very critical to find out the underlying reasonfor the persistent overgrowth of gingiva.Objective:To establish a rat model of the CsA-induced gingival overgrowth and identify theexpression and localization of MMP-2, CD147and CyPA in gingival tissues of CsA-treated rats by immunohistochemistry and Real-Time PCR.Methods:1. After extracting all left maxillary molars,40Sprague-Dawley rats underwent a2-week healing period. The animals were randomly divided into CsA-treated and controlgroups. CsA-treated rats received CsA by gastric feeding for4weeks, while the controlgroup received only mineral oil.2. Posttreatment4weeks, all animals were sacrificed, the macromorphologic andhistomorphometric of both side of the maxillary and mandibular gingivae were evaluated.The immunohistochemistry analysis of MMP-2, CD147and CyPA in gingival tissue wasperformed.3. Gingival tissue samples were collected from the2groups. Total RNA wasisolated and reverse transcription polymerase chain reaction (RT-PCR) was performedfor MMP-2, CD147and CyPA expression.Results:1、After2weeks of the treatment with CsA, part of the CsA-treated group rat’sgingival papillary overgrowth was erythematous and edematous, with a propensitytoward spontaneous subgingival hemorrhage. After4weeks of the treatment, the symptoms and signs included the gingival mucosa purple, gums thickening sphericalenlargement, gradually anorexia, emaciation, slowness of movement. Histologically, thebiopsy specimens demonstrated hyperplasia of the epithelium typified by mildhyperkeratosis, acanthosis, and elongation of rete pegs.2、The immunohistochemistry results showed intracellular and extracellular MMP-2in normal gingival tissues with intensity of higher labeling compared to the CsA-treatedgingival overgrowth tissue（sP<0.01）；but there was no significantly difference in CD147and CyPA between the two groups（P>0.05）.3、Compared with the control group, the mRNA expressive levels of MMP-2,CD147and CyPA were decreased significantly in the CsA-treated group（P<0.05）.Conclusions：We believe that the plaque is the relevant factor but not initiating factor of CIGO.The mechanism of CIGO, may be concerned with the formation of CsA-CyPA complexand competitive inhibition of the interaction between CyPAand CD147, blocking CD147upregulation of MMPs, leading to collagen degradation imbalance, and collagenaccumulation, causing gingival overgrowth.