Uncovering the molecular networks in periodontitis

Abstract

Periodontitis is a complex immune-inflammatory disease that results from a preestablished infection in gingiva, mainly due to Gram-negative bacteria that colonize deeper in gingival sulcus and latter periodontal pocket. Host inflammatory and immune responses have both protective and destructive roles. Although cytokines, prostaglandins, and proteases struggle against microbial burden, these molecules promote connective tissue loss and alveolar bone resorption, leading to several histopathological changes, namely destruction of periodontal ligament, deepening of periodontal pocket, and bone loss, which can converge to attain tooth loss. Despite the efforts of genomics, transcriptomics, proteomics/peptidomics, and metabolomics, there is no available biomarker for periodontitis diagnosis, prognosis, and treatment evaluation, which could assist on the established clinical evaluation. Nevertheless, some genes, transcripts, proteins and metabolites have already shown a different expression in healthy subjects and in patients. Though, so far, 'omics approaches only disclosed the host inflammatory response as a consequence of microbial invasion in periodontitis and the diagnosis in periodontitis still relies on clinical parameters, thus a molecular tool for assessing periodontitis lacks in current dental medicine paradigm. Saliva and gingival crevicular fluid have been attracting researchers due to their diagnostic potential, ease, and noninvasive nature of collection. Each one of these fluids has some advantages and disadvantages that are discussed in this review.

Keywords: Diagnosis; Gingival crevicular fluid; Periodontitis; Saliva; ‘Omics.

Figure 1

Overview of the major histopathological changes found in periodontitis. (A) A periodontally healthy site with the most important histological structures depicted. (B) A periodontally affected site showing an inflamed gingiva due to microbial colonization, a deepened periodontal pocket, attachment loss and loss of periodontium structures (bone and periodontal ligament). The purple circle illustrates a critical area of inflammation and disease progression. Images were adapted from Servier Medical Art (http://www.servier.com).

Figure 2

Evolution on the view of periodontitis pathogenesis and diagnosis since 1958. The time frame was built based on published reports [5, 10, 11, 20, 99-103].

Figure 3

Current view of periodontitis pathogenesis—a nonlinear model (1997) [10]. In the present model, microbial, genetic, and environmental factors play important roles in periodontitis pathogenesis. Besides, it recognizes the importance of host inflammatory and immune response and connective and bone tissue metabolism to the progression of periodontitis [2,3,10].

Figure 4

Cellular and molecular hallmarks of periodontitis—a summary scheme. In the presence of a microbial challenge, epithelial cells, fibroblasts, dendritic cells, leukocytes, and osteoclasts release inflammatory cytokines and chemokines that attract other leukocytes. MMPs are also released to allow leukocytes infiltration in periodontium. PMNs and dendritic cells activate both innate and acquired immune systems, which contributes to infection control through phagocytosis and destruction of bacteria [3, 10, 13]. The extensive release of cytokines, prostaglandins (PG), MMPs, and other proteases result in bone and connective tissue loss [13]. The tooth image was retrieved from Servier Medical Art (http://www.servier.com).

Figure 5

Network of genes, transcripts, and proteins differentially expressed in periodontitis built with the ClueGO tool. Red nodes represent upregulated molecular markers in periodontitis, while green nodes represent downregulated molecular markers. Enrichment analysis was performed with CluePedia: activation, green arrows; binding, blue arrows; expression, yellow arrows; and PTMs, pink arrows. Contributions of genomics, transcriptomics, and proteomics are shown with transparent purple, orange, and blue circles, respectively.