Coste de las alternativas
CAPÍTULO 5. MOBILIARIO URBANO
Periodontal disease is a multifactorial disease that is regulated by complex etiopathogenesis mechanisms. In this study, we covered many aspects of periodontal disease from both cellular and tissue changes. Gingival epithelium provides an early line of defense against bacteria in the gingival sulcus, while gingival connective tissue fibroblast plays an integral role in tissue remodeling and host responses. On the other hand, gingival tissues need to maintain glucose homeostasis to survive and act.
Genetic risk burdens are also of great significance in periodontal disease. Over the years, many candidate genes have been identified that either predispose or protect subjects from developing periodontal diseases. These genes include but not limited to IL-1, IL-6, Fc gamma receptor, TNF-α, human vitamin D receptor, MMP-1, TLRs, COX-2, and C-reactive protein genes (Laine et al., 2012; Zhang et al., 2011). Mixed results are reported and extents of risks conferred by genetic differences are still under debate. It has been widely accepted that genetic risks of periodontitis may depend on a mixed pool of genes. To search for more candidate genes for periodontal disease, we conducted a genome-wide association study and have generated many interesting findings. Many new candidate genes have been found to be associated with severities of periodontitis (Divaris et al., 2013). We also have unpublished data suggesting that polymorphisms of human genes are associated with bacterial colonization. PKP2 gene is one of those genes. 5 SNPs variants (rs6488099, rs4931044, rs2389107, rs7962334, rs7299220) of PKP2 gene are significantly associated with the highest colonization of P. gingivalis among 909
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subjects. In chapter 4, we have found that PKP2 expression is decreased in periodontitis gingival biopsies and P.gingivalis degradation is a potential driven force. Therefore, we further generate a hypothesis that hosts with differential PKP2 SNPs variants respond differently to P. gingivalis, which could predispose them to periodontal disease.
For the future directions, we can acquire primary gingival epithelial cells from gingival explants of periodontitis and healthy subjects from designated genetic backgrounds. After genotyping each individual’s PKP2 SNPs, we will evaluate gingival epithelial cells for cell proliferation, attaching and spreading, and barrier activity. As demonstrated in Figure 4.7, we have already established a system that allows us to use different experimental approaches to test for potential roles of PKP2 SNPs variants. Similarly, hosts with differential PKP2 DNA
methylation patterns may respond differently to P.gingivalis or other periodontal pathogens. In human gingival epithelial cells, TLR2 DNA hypermethylation is associated with dampened immune responses to P. gingivalis (Benakanakere et al., 2015). Although we did not capture a significant hypermethylation pattern of PKP2 gene in gingival biopsies, we did observe an elevation of overall methylation after a short term of bacterial challenges. For the future study, we can group gingival epithelial cells based on their methylation pattern and examine potential high responders or low responders. Additionally, a long-term bacterial culture system should be established to investigate the alteration of DNA methylation machinery affected by periodontal pathogens.
PKP2 exerts multiple functions beyond being a desmosomal structural protein. PKP2 induces the phosphorylation of epidermal growth factor receptor (EGFR) to promote cell proliferation (Arimoto et al., 2014; Kazlauskas, 2014). Deficient PKP2 in keratinocytes leads to delayed migration through altered focal adhesion (Koetsier et al., 2014). An additional study has shown
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that PKP2 directly interacts with β-catenin to potentiate TCF/LEF1-mediated transcription of target genes (Chen et al., 2002). PKP2 also associates with RNA polymerase III in the nucleus (Mertens et al., 2001). Since pol III regulates tRNA, rRNA 5S, and some small RNAs, PKP2 may present post-translational functions as well.
We have data showing that PKP2 is also potently expressed in gingival fibroblast, where DSG1 is lacking. Therefore, PKP2 may present multiple roles in periodontal disease, which is another direction to pursue.
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