Association of gene polymorphisms for plasminogen activators with alveolar bone loss

DeCarlo, Arthur A.; Grenett, Hernan E.; Park, J.; Balton, W.; Cohen, Jared; Hardigan, Patrick C.

doi:10.1111/j.1600-0765.2006.00949.x

Cited by 9 publications

(8 citation statements)

References 32 publications

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“…There was significantly less macrophage infiltration within tumours of uPA knockout (−/−) mice compared with wild‐type (WT) mice 58 . Several studies have demonstrated uPA activity in human gingival tissue and in gingival crevicular fluid 59 , 60 , 61 , and polymorphisms in the uPA gene have been found to be associated with periodontal bone loss 62 . Despite these findings, the role of uPA in a P. gingivalis ‐induced periodontitis model has not been studied.…”

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confidence: 99%

GM‐CSF and uPA are required for Porphyromonas gingivalis‐induced alveolar bone loss in a mouse periodontitis model

et al. 2015

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) and urokinase-type plasminogen activator (uPA) can contribute to the progression of chronic inflammatory diseases with possible involvement of macrophages. In this study, we investigated the role of both GM-CSF and uPA in Porphyromonas gingivalis-induced experimental periodontitis using GM-CSF-/- and uPA-/- mice. Intra-oral inoculation of wild-type (WT) C57BL/6 mice with P. gingivalis resulted in establishment of the pathogen in plaque and a significant increase in alveolar bone resorption. The infected mice also exhibited a CD11b(+) CD86(+) macrophage infiltrate into the gingival tissue, as well as P. gingivalis-specific pro-inflammatory cytokine and predominantly IgG2b antibody responses. In comparison, intra-oral inoculation of P. gingivalis did not induce bone resorption and there was significantly less P. gingivalis recovered from plaque in GM-CSF-/- and uPA-/- mice. Furthermore, P. gingivalis did not induce a macrophage gingival infiltrate or activate isolated peritoneal macrophages from the gene-deficient mice. Pro-inflammatory P. gingivalis-specific T-cell cytokine responses and serum interferon-gamma (IFN-γ) and IgG2b concentrations were significantly lower in GM-CSF-/- mice. In uPA-/- mice, T-cell responses were lower but serum IFN-γ and IgG2b levels were comparable with WT mice levels. These results suggest that GM-CSF and uPA are both involved in the progression of experimental periodontitis, possibly via a macrophage-dependent mechanism(s).

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confidence: 99%

GM‐CSF and uPA are required for Porphyromonas gingivalis‐induced alveolar bone loss in a mouse periodontitis model

et al. 2015

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“…Interestingly, spontaneous development of periodontitis in plasminogen‐null and tPA/uPA double‐deficient mice closely resembles the pathological progression of the human disease . Furthermore, polymorphisms in the genes encoding uPA and PAI‐1 are associated with periodontal bone loss . These observations strongly suggest that plasmin activity is essential for periodontal health in humans.…”

Section: Discussionmentioning

confidence: 93%

“…13 In humans, genetic 43 or induced 12 deficiencies in plasmin activity often (34% in congenital type I plasminogen deficiency) lead to ligneous conjunctivitis in most cases associated with periodontium destruction (ligneous periodontitis). 44 These observations strongly suggest that plasmin activity is essential for periodontal health in humans. 13 Furthermore, polymorphisms in the genes encoding uPA and PAI-1 are associated with periodontal bone loss.…”

Section: Discussionmentioning

confidence: 96%

“…13 Furthermore, polymorphisms in the genes encoding uPA and PAI-1 are associated with periodontal bone loss. 44 These observations strongly suggest that plasmin activity is essential for periodontal health in humans. In this context, the discovery that T. forsythia, the major periodontal pathogen in humans, produces the very efficient serpin-type plasmin inhibitor miropin is fascinating.…”

Section: Discussionmentioning

confidence: 96%

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Plasmin inhibition by bacterial serpin: Implications in gum disease

et al. 2019

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Tannerella forsythia is a periodontopathogen that expresses miropin, a protease inhibitor in the serpin superfamily. In this study, we show that miropin is also a specific and efficient inhibitor of plasmin; thus, it represents the first proteinaceous plasmin inhibitor of prokaryotic origin described to date. Miropin inhibits plasmin through the formation of a stable covalent complex triggered by cleavage of the Lys 368 -Thr 369 (P2-P1) reactive site bond with a stoichiometry of inhibition of 3.8 and an association rate constant (k ass ) of 3.3 × 10 5 M −1 s −1 . The inhibition of the fibrinolytic activity of plasmin was nearly as effective as that exerted by α 2 -antiplasmin. Miropin also acted in vivo by reducing blood loss in a mice tail bleeding assay. Importantly, intact T. forsythia cells or outer membrane vesicles, both of which carry surface-associated miropin, strongly inhibited plasmin. In intact bacterial cells, the antiplasmin activity of miropin protects envelope proteins from plasmin-mediated degradation. In summary, in the environment of periodontal pockets, which are bathed in gingival crevicular fluid consisting of 70% of blood plasma, an abundance of T. forsythia in the bacterial biofilm can cause local inhibition of fibrinolysis, which could have possible deleterious effects on the tooth-supporting structures of the periodontium. K E Y W O R D Sfibrinolysis, plasmin, periodontitis, serpin, Tannerella forsythia 620 |

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“…Additionally, polymorphisms in the genes for uPA and one of its inhibitors have been associated with periodontal bone loss (28). However, the role of uPA in PD has not been defined.…”

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confidence: 99%

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

Fleetwood

O'Brien-Simpson

Veith

et al. 2015

Journal of Biological Chemistry

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Association of gene polymorphisms for plasminogen activators with alveolar bone loss

Abstract: The urokinase plasminogen activator (BamHI) and plasminogen activator inhibitor type 1 (HindIII) genotypes may serve as useful markers for heritability of bone loss associated with periodontal disease.

Cited by 9 publications

References 32 publications

GM‐CSF and uPA are required for Porphyromonas gingivalis‐induced alveolar bone loss in a mouse periodontitis model

GM‐CSF and uPA are required for Porphyromonas gingivalis‐induced alveolar bone loss in a mouse periodontitis model

Plasmin inhibition by bacterial serpin: Implications in gum disease

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

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