Pathogenesis of periodontitis - A potential role for epithelial-mesenchymal transition

Abstract

Epithelial mesenchymal transition (EMT) is a process comprising cellular and molecular events which result in cells shifting from an epithelial to a mesenchymal phenotype. Periodontitis is a destructive chronic disease of the periodontium initiated in response to a dysbiotic microbiome, and dominated by Gram-negative bacteria in the subgingival niches accompanied by an aberrant immune response in susceptible subjects. Both EMT and periodontitis share common risk factors and drivers, including Gram-negative bacteria, excess inflammatory cytokine production, smoking, oxidative stress and diabetes mellitus. In addition, periodontitis is characterized by down-regulation of key epithelial markers such as E-cadherin together with up-regulation of transcriptional factors and mesenchymal proteins, including Snail1, vimentin and N-cadherin, which also occur in the EMT program. Clinically, these phenotypic changes may be reflected by increases in microulceration of the pocket epithelial lining, granulation tissue formation, and fibrosis. Both in vitro and in vivo data now support the potential involvement of EMT as a pathogenic mechanism in periodontal diseases which may facilitate bacterial invasion into the underlying gingival tissues and propagation of inflammation. This review surveys the available literature and provides evidence linking EMT to periodontitis pathogenesis.

Keywords: Cell adhesion; Epithelial mesenchymal transition; Growth factor; Periodontal pathogen; Periodontitis; Transcription factor.

Fig. 1

Growth of the EMT-related literature. The first experimental analysis of epithelial–mesenchymal transition (EMT) in development was published in 1968. The relationship of EMT to growth factors was identified in 1989 and the transcriptional regulation of EMT was identified in 1994. More recent studies link EMT to metastasis, organ fibrosis and stem cells.

Fig. 2

Types of epithelial-mesenchymal transition (EMT). Type 1 EMT is evident during embryonic life and considered as an integral mechanism for the gastrulation and development of the organs. During adult life, type 2 and 3 EMT are classified as pathological processes responsible for the fibrosis of organs and cancer metastasis, respectively.

Fig. 3

Progression of molecular and cellular events in EMT. A) Under homeostatic conditions, epithelial cells form coherent epithelial sheets and express molecules uniquely associated with the epithelial-phenotype, such as E-cadherin, β-catenin, occludins, and α6β4 integrins. B) Exposure of epithelial cells to EMT-inducer(s), e.g., cytokines or Gram-negative bacterial components, triggers the EMT process. Early events include loss of apico-basal polarity followed by downregulation of attachment proteins concomitant with up-regulation of mesenchymal proteins, such as vimentin. At this stage, both epithelial and mesenchymal biomarkers are co-expressed in the same cell and this is defined as partial EMT. C) Prolonged exposure to EMT-inducers results in a complete loss of the epithelial phenotype and acquisition of a mesenchymal phenotype. Transitioned cells exhibit increased motility together with increased expression of matrix metalloproteinases that degrade the basement membrane, thereby, facilitating migration of these mesenchymal cells to the underlying connective tissue.

Fig. 4

Pathogenesis of periodontitis. Dysbiosis of subgingival microbiome results in an increased populations of red and orange bacteria such as Porphyromonas gingivalis and Fusobacterium nucleatum. The virulence factors described in the main text body trigger an inflammatory response mainly via Toll-like receptor signaling which activates intracellular NF-κB which in turn increases interleukin (IL) production. IL-8, in particular, acts as a chemotactic agent for inflammatory cells such as neutrophils and macrophages, recruiting them from nearby blood vessels. Cellular (T-cells) and humoral (B-cells) immune cells also increase in numbers due to the chemotactic gradients generated in association with chronic inflammation. These inflammatory events lead to further escalation of inflammatory mediator production which can compromise the integrity of the epithelial pocket lining and drive the EMT process. Additionally, tissue destruction and bone resorption increase due to overexpression of matrix metalloproteinases and RANKL, respectively. Subsequent exposure of the underlying connective tissue and increased vascular permeability facilitate the entry of periodontal pathogens and/or inflammatory cytokines to the circulation thereby contributing to the impact of periodontitis on systemic diseases.