Expression of Epithelial-Mesenchymal Transition Associated Markers in Peri-implant Tissues

Overview

Peri-implantitis is an inflammation of bacterial etiology characterized by inflammation of mucous membranes and bone loss around the dental implant. A specific dental plaque bacteria could stimulate host cells, including the junctional epithelium, to secrete a range of pro-inflammatory cytokines involved in initiating the epithelial-mesenchymal transition (EMT) process. EMT has been described as the transdifferentiation of epithelial cells into motile mesenchymal cells. Moreover, cytokines and bacterial products have been highlighted as EMT-predisposing factors. The EMT process could render epithelial cells to lose their cell-cell adhesion and cell polarity that lend these cells to lose their function as an integrated epithelial barrier. E-cadherin is a calcium-dependent cell adhesion molecule that establishes cell-cell adhesion that plays a critical role in maintaining a barrier function in the human epithelium, including gingiva. The loss of E-cadherin is one of the most common biological indicators for EMT. In contrast, vimentin is an intermediate filament expressed in mesenchymal cells and is a canonical marker for EMT, which also promotes cell motility and an invasive phenotype. It is largely reported that EMT is regulated by various transcriptional factors such as Snail Family Transcriptional Repressor SNAIL1 and SNAIL2, zinc-finger E-box-binding (ZEB)1 and ZEB2 and TWIST transcription factors that suppress epithelial marker genes, and activate genes related with the mesenchymal phenotype. Recently, in vivo study has investigated the level of EMT markers in the gingival tissues of periodontitis patients. It was found that the expression of E-cadherin was downregulated while vimentin expression was upregulated. Despite the similarities and differences between the pathogenesis of periodontal and peri-implant diseases, the role of dental biofilm in the etiopathogenesis of the aforementioned diseases was studied largely. While it is now accepted that EMT may potentially play a role in periodontal disease pathogenicity, the possible role of EMT in the disintegration of the peri-implant epithelial barrier and the pathogenesis of peri-implant disease has not yet been investigated.

Dental implant therapy is a reliable treatment for replacing missing or lost teeth. Despite its high survival and success rates, it has long been realized that biological complications could occur in osseointegrated implants, collectively termed peri-implant diseases. Peri-implantitis is the second most common form of peri-implant disease, and its prevalence was shown to be 10% to 30% at the implant level and 20% at the patient level. Peri-implantitis is an inflammation of bacterial etiology characterized by inflammation of mucous membranes and bone loss around the dental implant. Clinically, it shows signs of inflammation, bleeding on probing and/or suppuration, increased probing depths, and/or recession of the mucosal margin in addition to radiographic bone loss compared to previous examinations. Inflammatory peri-implant lesions usually start due to the accumulation of bacterial plaque and progress in a faster pattern compared to periodontitis. It has been reported that specific dental plaque bacteria could stimulate host cells, including the junctional epithelium, to secrete a range of pro-inflammatory cytokines involved in initiating the epithelial-mesenchymal transition (EMT) process. EMT has been described as the transdifferentiation of epithelial cells into motile mesenchymal cells. It is considered integral in the development, wound healing, and stem cell behavior and contributes pathologically to fibrosis and cancer progression. Moreover, cytokines and bacterial products have been highlighted as EMT-predisposing factors. It has been proposed that the EMT process could render epithelial cells to lose their cell-cell adhesion and cell polarity that lend these cells to lose their function as an integrated epithelial barrier. Consequently, bacterial invasion into the underlying connective tissues could occur, and epithelial cells are assumed to have a mesenchymal cell phenotype through the upregulation of mesenchymal markers and downregulation of epithelial markers. E-cadherin is a calcium-dependent cell adhesion molecule that establishes cell-cell adhesion, known as the adherens junction, playing a critical role in maintaining a barrier function in the human epithelium, including gingiva. The loss of E-cadherin is one of the most common biological indicators for EMT. In contrast, vimentin is an intermediate filament expressed in mesenchymal cells and is a canonical marker for EMT, which also promotes cell motility and an invasive phenotype. It has been shown that the level of vimentin protein expression is significantly increased by P. gingivalis infection. It is largely reported that EMT is regulated by various transcriptional factors such as Snail Family Transcriptional Repressor SNAIL1 and SNAIL2, zinc-finger E-box-binding (ZEB)1 and ZEB2 and TWIST transcription factors that suppress epithelial marker genes, and activate genes related with the mesenchymal phenotype. These transcriptional factors act as E-cadherin repressors and play a pivotal role in development, fibrosis, and cancer. Several signaling pathways collaborate in the beginning and advancement of EMT, and they can promote SNAIL1 expression and transforming growth factor beta. Recently, in vivo study has investigated the level of EMT markers in the gingival tissues of periodontitis patients. It was found that the expression of E-cadherin was downregulated while vimentin expression was upregulated. Accordingly, the authors proposed that EMT may potentially play an essential role in the pathogenesis and prognosis of periodontal disease. Much of the etiology and pathogenesis of peri-implant disease was acknowledged to be similar to periodontitis since both share many clinical and radiologic features in common for destructive inflammatory diseases. However, in contrast to periodontitis, peri-implantitis lesions show a poorer vascular supply, a lack of connective tissue encapsulation of large inflammatory cell infiltrates, and a differing cell profile with high numbers of B cells, osteoclasts, and neutrophils. This suggests that peri-implantitis has a similar aetiopathogenesis to periodontitis but also notable differences; its progression seems faster and more aggressive. Despite these similarities and differences between the pathogenesis of periodontal and peri-implant diseases, the role of dental biofilm in the etiopathogenesis of the aforementioned diseases was studied largely. While it is now accepted that EMT may potentially play a role in periodontal disease pathogenicity, the possible role of EMT in the disintegration of the peri-implant epithelial barrier and the pathogenesis of peri-implant disease has not yet been investigated.