Participation of DPPIV produced by P.gingivalis in periodontal disease.

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Porphyromonas gingivalis is a major pathogen associated with adult periodontitis and is also suggested to be an etiologic agent of systemic diseases such as aspiration pneumonia in the elder. This bacterium produces dipeptidyl aminopeptidase IV (DPPIV), which is a serine protease that cleaves X-Pro or X-Ala dipeptide from the N-terminal end of the polypeptide chain. Our purpose of this investigation was to clarify pathological functions of P.gingivalis DPPIV as a virulence factor. We cloned the gene (dpp) coding for DPPIV from P.gingivalis, constructed an isogenic dpp null mutant, and subjected to animal experiments. The wild type showed higher virulence than the mutant, as revealed by a higher mortality, a slower recovery from illness, and a greater extent of lesion development. Destruction of the connective tissue caused by the wild type was severer than that by the mutant as observed histopathologically. We then investigated the molecular mechanisms by which this enzyme participated in the tissue destruction. This enzyme possessed a gelatinase activity and accelerated gelatin degradation by host-derived gelatinase, matrix metalloproteinases (MMP-2 and MMP-9). Type I collagen cleaved with host-derived collagenase, MMP-1 or MMP-8, was further degraded by DPPIV.This enzyme bound to fibronectin and mediated adhesion of P.gingivalis to fibronectin. Adhesion was not detected in the dpp-null mutant. The activity was restored by introducing not only the wild type dpp gene but the mutant gene, in which the amino acid responsible for DPPIV exopeptidase activity, Ser 593, was altered by site-directed mutagenesis. Adhesion of human gingival fibroblast and NIH3T3 cells to fibronectin was inhibited by DPPIV in a dose dependent manner. These results exhibit novel biological activities of DPPIV and indicate the pathological roles for progression of periodontitis and other systemic diseases.