Objective: Identify biologic pathways that are altered in all forms of GO to reveal mechanisms driving gingival enlargement.
Method: Gingival biopsies (n=23) were obtained from affected individuals with 4 genetically distinct forms of Hereditary Gingival Fibromatosis (HGF), individuals with drug induced GO (cyclosporine and calcium channel blocker) and controls without GO. Total gingival RNA was extracted with Trizol, RNA quality assessed with Agilent Bioanalyzer and gene expression determined with Codelink Whole Human Genome Arrays. Gene expression was analyzed using Geospiza Genesifter (V3.7) integrated gene ontology and pathway analysis. Protein-protein interactions were evaluated using STRING 9.0. Statistical analyses included t-test with multiple comparisons correction, ANOVA and gene expression thresholds (>20.0), adjusted p value cutoffs < 0.05.
Result: 476 genes were differentially expressed >20 fold in all forms of gingival overgrowth. The most up-regulated genes included S100A7, IL-8, CBL, P13, ITGA9, ITGAD, DEFB4. The most down-regulated genes included >15 epidermal differentiation complex genes, including loricrin and late cornified-envelope genes, as well as genes controlling cell differentiation, particularly epidermal. Ontology analyses of differentially expressed genes identified similar changes in expression patterns for biologic processes and molecular functions responding to biotic stimuli in all GO biopsies, regardless of etiologic type. Cluster analysis and Principal Component Analysis of differentially expressed biotic stimulus response genes delineated control samples from drug induced and HGF GO. STRING analysis identified a predominant pathway linking ligand, cell surface receptor and signal transduction for a majority of the most up-regulated genes.
Conclusion: Gingival tissues from diverse forms of GO show consistent up-regulation of genes linked to signal transduction and cell proliferation and down-regulation of cell differentiation genes. These findings provide a common biologic framework to explain the increased gingival tissue associated with these different forms of GO.