Relationship between periodontal disease and systemic diseases: molecular mechanisms and novel therapy discovery

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To establish the molecular basis of the possible linkage between periodontal diseases and a variety of systemic diseases such as atherosclerosis, obesity, diabetes, and preterm birth and fetal death, we used various animal models and different cell types and manipulated the endolysosomal aspartic proteinase cathepsin E (CatE) as a host-derived protease and gingipains (GP) as a periodontopathogen-derived protease. In this study, we first found that CatE plays a crucial role in host defense against infection with Porphyromonas gingivalis, a major etiological bacterium of adult periodontal disease through proper trafficking and cell surface expressionof Toll-like receptors such as TLR4 in macrophages. Second, GP mediates atherosclerosis progression accelerated by P. gingivalisinfection through selective proteolysis of apolipoprotein B-100 in LDL cholesterol. Third,GP acts as a strong virulence factor to induce preterm birth and low birth weight through the enhancement of immune responses to pregnant mice infected with P. gingivalis. Fourth, CatE plays a crucial role in normal development of adipose tissues through biochemical analysis of CatE-/-mice that were fed a high-fat diet as an obesity mouse model. Forth, using techniques of cDNA display, selection-by-function, γ-ligation-based block shuffling and others, we generated peptide inhibitors for CatE and GP. The newly developed inhibitors for each enzyme showed an IC50 of nM order and high selectivity. This method is thus expected to be widely applicable for the development of peptide inhibitors of various proteases.