Molecular and Clinical Aspects of Drug-induced Gingival Overgrowth

Abstract

Drug-induced gingival overgrowth is a tissue-specific condition and is estimated to affect approximately one million North Americans. Lesions occur principally as side-effects from phenytoin, nifedipine, or ciclosporin therapy in approximately half of the people who take these agents. Due to new indications for these drugs, their use continues to grow. Here, we review the molecular and cellular characteristics of human gingival overgrowth lesions and highlight how they differ considerably as a function of the causative drug. Analyses of molecular signaling pathways in cultured human gingival fibroblasts have provided evidence for their unique aspects compared with fibroblasts from the lung and kidney. These findings provide insights into both the basis for tissue specificity and into possible therapeutic opportunities which are reviewed here. Although ciclosporin-induced gingival overgrowth lesions exhibit principally the presence of inflammation and little fibrosis, nifedipine-and especially phenytoin-induced lesions are highly fibrotic. The increased expression of markers of gingival fibrosis, particularly CCN2 [also known as connective tissue growth factor (CTGF)], markers of epithelial to mesenchymal transition, and more recently periostin and members of the lysyl oxidase family of enzymes have been documented in phenytoin or nifedipine lesions. Some oral fibrotic conditions such as leukoplakia and oral submucous fibrosis, after subsequent additional genetic damage, can develop into oral cancer. Since many pathways are shared, the study of gingival fibrosis and comparisons with characteristics and molecular drivers of oral cancer would likely enhance understandings and functional roles of molecular drivers of these oral pathologies.

Dental plaque–induced gingival conditions

“…There are an assortment of medications that have been reported to affect the size of the gingival tissues . In the literature, the drugs primarily associated with gingival tissue enlargement have included the antiepileptic drugs phenytoin and sodium valproate, certain calcium channel–blocking drugs (e.g., nifedipine, verapamil, diltiazem, amlodipine, felodipine), immunoregulating drugs (e.g., ciclosporine), and high‐dose oral contraceptives . For drug‐influenced gingival conditions, plaque bacteria in conjunction with the drug are necessary to produce a gingival response.…”

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

“…1 GF may also develop from environmental exposure such as a side effect of medications including anticonvulsants (i.e., phenytoin), immunosuppressants (i.e., cyclosporine), or calcium channel blockers (i.e., nifedipine, diltiazem, and verapamil). 2,3 The initial differential diagnosis for GF also includes chronic hyperplastic gingivitis, leukemic infiltrate, and some systemic diseases such as Crohn disease (MIM: 266600), neurofibromatosis (MIM: 162200), primary amyloidosis (MIM: 204850), sarcoidosis (MIM: 181000), scurvy (MIM: 240400), and Wegener granulomatosis (MIM: 608710) that have been associated with gingival overgrowth. 4 HGF is the most common genetic form of GF which is usually transmitted as an autosomal-dominant trait.…”

Nifedipine and phenytoin induce matrix synthesis, but not proliferation, in intact human gingival connective tissue ex vivo

“…As stated above, DIGE arising from different drugs is associated with varying levels of fibrosis and Human gingival connective tissues cultured with nifedipine (100 ng/ml), phenytoin (30 μg/ml), or without the drug for 2 weeks were stained using terminal deoxynucleotidyl transferase-mediated dUTPbiotin nick-end-labeling (TUNEL). a. inflammatory cell infiltration (Trackman and Kantarci 2015), but systems to investigate the molecular mechanisms underlying these differences have been lacking, which our ex vivo model overcomes.…”

“…Data represents mean fold hydroxyproline levels±STD relative to control (no drug) condition of three independent experiments in triplicates. Data was analyzed using one-way ANOVA with Bonferroni's multiple comparisons test (*p<0.05) several pathways converge to upregulate the protein (for a comprehensive review, see (Trackman and Kantarci 2015), but whether periostin is increased through similar mechanisms is yet to be determined.…”