On the Cellular and Molecular Mechanisms of Drug-Induced Gingival Overgrowth

Abstract

Introduction:Gingival overgrowth has been linked to multiple factors such as adverse drug effects, inflammation, neoplastic processes, and hereditary gingival fibromatosis. Drug-induced gingival overgrowth is a well-established adverse event. In early stages, this gingival enlargement is usually located in the area of the interdental papilla. Histologically, there is an increase in the different components of the extracellular matrix.Objective:The aim of this manuscript is to describe and analyze the different cellular and molecular agents involved in the pathogenesis of Drug-induced gingival overgrowth.Method:A literature search of the MEDLINE/PubMed database was conducted to identify the mechanisms involved in the process of drug-induced gingival overgrowth, with the assistance of a research librarian. We present several causal hypotheses and discuss the advances in the understanding of the mechanisms that trigger this gingival alteration.Results: In vitro studies have revealed phenotypic cellular changes in keratinocytes and fibroblasts and an increase of the extracellular matrix with collagen and glycosaminoglycans. Drug-induced gingival overgrowth confirms the key role of collagenase and integrins, membrane receptors present in the fibroblasts, due to their involvement in the catabolism of collagen. The three drug categories implicated: calcineuron inhibitors (immunosuppressant drugs), calcium channel blocking agents and anticonvulsant drugs appear to present a multifactorial pathogenesis with a common molecular action: the blockage of the cell membrane in the Ca2+/Na+ ion flow. The alteration of the uptake of cellular folic acid, which depends on the regulated channels of active cationic transport and on passive diffusion, results in a dysfunctional degradation of the connective tissue. Certain intermediate molecules such as cytokines and prostaglandins play a role in this pathological mechanism. The concomitant inflammatory factor encourages the appearance of fibroblasts, which leads to gingival fibrosis. Susceptibility to gingival overgrowth in some fibroblast subpopulations is due to phenotypic variability and genetic polymorphism, as shown by the increase in the synthesis of molecules related to the response of the gingival tissue to inducing drugs. The authors present a diagram depicting various mechanisms involved in the pathogenesis of drug-induced gingival overgrowth.Conclusion:Individual predisposition, tissue inflammation, and molecular changes in response to the inducing drug favor the clinical manifestation of gingival overgrowth.

Immunohistochemical analysis of the role connective tissue growth factor in drug-induced gingival overgrowth in response to phenytoin, cyclosporine, and nifedipine

“…Similar to the previous literature,[ 1 3 ] all tissues were stained with H and E. The sections reveal gingival hyperplasia with dense, elongated, and thin rete pegs inserted in deep connective tissue, which were more in phenytoin group followed by nifedipine and cyclosporine group. All control slides reveal histologically healthy gingiva in the absence of hyperplasia and fibrosis [Figures 6 – 15 ].…”

“…In concurrence with the current study, Uzel[ 4 ] et al stated about the elevated level of CTGF in DIGO in various fibrotic disorders. However, as the number of analysis to statistically document the role of CTGF in DIGO[ 1 3 ] has been limited, we undertook the present study to further strengthen the data on the role of CTGF in the expression of drug-induced gingival enlargement.…”

“…Similar to the previous studies,[ 1 3 ] the gingival samples for control group were taken from healthy patients who were treated for preprosthetic crown lengthening.…”

“…Hence, LAB-SA method has been used in the present study. Previous research[ 3 ] on the role of CTGF has used the first generation avidin-biotin method (ABC method).…”

“…The study group showed a statistical significance ( P < 0.05) in agreement with the previous study by Uzel et al . [ 3 ]…”