The Role of Gingipains in the Pathogenesis of Periodontal Disease

Abstract

Gingipains are trypsin-like cysteine proteinases produced by Porphyromonas gingivalis, a major causative bacterium of adult periodontitis. HRgpA (95 kDa) and RgpB (50 kDa), products of 2 distinct but related genes, rgpA and rgpB, respectively, are specific for Arg-Xaa peptide bonds. Kgp, a product of the kgp gene, is specific for Lys-Xaa bonds. HRgpA and Kgp are non-covalent complexes containing separate catalytic and adhesion/ hemagglutinin domains, while RgpB has only a catalytic domain with a primary structure essentially identical to that of the catalytic subunit of HRgp. HRgpA and RgpB induce vascular permeability enhancement through activation of the kallikrein/kinin pathway and activate the blood coagulation system, which, respectively, are potentially associated with gingival crevicular fluid production and progression of inflammation leading to alveolar bone loss in the periodontitis site. Kgp is the most potent fibrinogen/fibrin degrading enzyme of the 3 gingipains in human plasma and is involved in the bleeding tendency at the diseased gingiva. HRgpA activates coagulation factors and degrades fibrinogen/fibrin more efficiently than RgpB due to the adhesion/hemagglutinin domains, which have affinity for phospholipids and fibrinogen. Gingipains degrade macrophage CD14, thus inhibiting activation of the leukocytes through the lipopolysaccharide (LPS) receptor, and thereby facilitating sustained colonization of P. gingivalis. Gingipains play a role in bacterial housekeeping and infection, including amino acid uptake from host proteins and fimbriae maturation. Based on the important activities of gingipains in the bacterial infection and the pathogenesis of periodontitis, the bacterial proteinases can be targets for periodontal disease therapy. Immunization with RgpB, HRgpA, or a portion of HRgpA catalytic domain attenuated P. gingivalis induced disorders in mice. In addition, a trypsin-like proteinase inhibitor retarded P. gingivalis growth specifically. Gingipains are potent virulence factors of P. gingivalis, and are likely to be associated with the development of periodontitis. It is, therefore, suggested that gingipain inhibition by vaccination and gingipain-specific inhibitors is a useful therapy for adult periodontitis caused by P. gingivalis infection.

Effects of sodium bicarbonate on butyric acid-induced epithelial cell damage in vitro

“…have been identified as important pathogens of periodontitis (1)(2)(3). Several virulence factors are associated with the pathogenicity of these bacteria, including lipopolysaccharide, fimbriae, hemagglutinin, hemolysin, and proteases (4)(5)(6)(7)(8). In addition, short-chain fatty acids such as butyric acid have been detected in periodontal pockets and are thought to be involved in the initiation and progression of periodontal disease (9).…”

Porphyromonas gingivalis-derived RgpA-Kgp Complex Activates the Macrophage Urokinase Plasminogen Activator System

“…P. gingivalis gingipains are powerful proteolytic enzymes that can degrade host proteins but can also activate host pathways. This unique ability allows P. gingivalis to generate nutrients in the form of tissue breakdown products and to subvert the host immune response, leading to periodontal inflammation and dysbiosis (21,22). uPA has been identified in inflamed periodontal tissue (26) and in the gingival crevicular fluid (27).…”

“…Major virulence factors produced by P. gingivalis are the trypsin-like cysteine proteinases called gingipains (22). The gingipains comprise the arginine-specific (RgpA and RgpB) and the lysine-specific (Kgp) proteinases based on their ability to cleave Arg-Xaa or Lys-Xaa peptide bonds, respectively (22).…”

“…The gingipains comprise the arginine-specific (RgpA and RgpB) and the lysine-specific (Kgp) proteinases based on their ability to cleave Arg-Xaa or Lys-Xaa peptide bonds, respectively (22). RgpA and Kgp form an extracellular cysteine protease complex (RgpA-Kgp complex) common to all characterized P. gingivalis strains and is a major factor contributing to its pathogenicity (23,24).…”

HtrA in Porphyromonas gingivalis can regulate growth and gingipain activity under stressful environmental conditions

“…This organism is also associated with other systemic diseases, including atherosclerosis (reviewed by Okuda & Ebihara, 1998;Teng et al, 2002;Kinane & Marshall, 2001). The major virulence factors of P. gingivalis, the gingipains, possess high levels of proteolytic activity and have been the focus of much attention (Genco et al, 1999;Imamura, 2003;Nakagawa et al, 2003). The major gingipains are extracellular and/or cell-associated.…”