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.

Keywords: cell signaling; collagen(s); connective tissue biology; gingiva; inflammation; innate immunity.

Figure 1.

Relationship among inflammation, fibrosis, and drug treatments which cause gingival overgrowth in humans. The left side of represents high fibrosis which is accompanied by high CCN2 expression, while the right side represents high inflammation and low fibrosis (Uzel et al. 2001).

Figure 2.

Summary of signal transduction relationships in human gingival fibroblasts compared with lung fibroblasts. Unique aspects are indicated. ALK5, EP2, and EP3 are receptors that mediate signaling by TGF-β and prostaglandin E₂ (PGE₂); * high in gingival fibroblasts only; || high in lung fibroblasts only (Black et al. 2007; Thompson et al. 2010).

Figure 3.

Model for relationships between active protein kinase A and GSK3β. The proposed model may account for the unique sensitivity of (A) human gingival fibroblast expression of TGF-β-stimulated CCN2 to GSK3β inhibitors compared with (B) lung fibroblasts (Bahammam et al. 2013).