Porphyromonas gingivalis-derived RgpA-Kgp Complex Activates the Macrophage Urokinase Plasminogen Activator System: IMPLICATIONS FOR PERIODONTITIS* |
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| Authors: | Andrew J. Fleetwood Neil M. O'Brien-Simpson Paul D. Veith Roselind S. Lam Adrian Achuthan Andrew D. Cook William Singleton Ida K. Lund Eric C. Reynolds John A. Hamilton |
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| Affiliation: | From the ‡Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.;the §Oral Health Cooperative Research Centre, Melbourne Dental School, University of Melbourne, Victoria 3010, Australia, and ;the ¶Finsen Laboratory, Rigshospitalet and ;the ‖Biotech Research and Innovation Centre, Copenhagen University, 1165 Copenhagen, Denmark |
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| Abstract: | Urokinase plasminogen activator (uPA) converts plasminogen to plasmin, resulting in a proteolytic cascade that has been implicated in tissue destruction during inflammation. Periodontitis is a highly prevalent chronic inflammatory disease characterized by destruction of the tissue and bone that support the teeth. We demonstrate that stimulation of macrophages with the arginine- and lysine-specific cysteine protease complex (RgpA-Kgp complex), produced by the keystone pathogen Porphyromonas gingivalis, dramatically increased their ability to degrade matrix in a uPA-dependent manner. We show that the RgpA-Kgp complex cleaves the inactive zymogens, pro-uPA (at consensus sites Lys158-Ile159 and Lys135-Lys136) and plasminogen, yielding active uPA and plasmin, respectively. These findings are consistent with activation of the uPA proteolytic cascade by P. gingivalis being required for the pathogen to induce alveolar bone loss in a model of periodontitis and reveal a new host-pathogen interaction in which P. gingivalis activates a critical host proteolytic pathway to promote tissue destruction and pathogen virulence. |
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| Keywords: | extracellular matrix macrophage periodontal disease plasmin plasminogen |
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