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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Reduction of arthritis severity in protease-activated receptor-deficient mice.

OBJECTIVE: Protease-activated receptor 1 (PAR-1) is the cell surface receptor for thrombin. It is unclear whether thrombin contributes to inflammation other than by effects on coagulation. We investigated the proinflammatory participation of PAR-1 in antigen-induced arthritis (AIA). METHODS: Arthritis was induced by intraarticular injection of methylated bovine serum albumin (mBSA) in preimmunized PAR-1-deficient (PAR-1(-/-)) and wild-type (WT) mice. The disease was assessed after 7 days by histologic examination of knee joints after decalcification and Safranin O/toluidine blue staining. Serum levels of anti-mBSA IgG, interferon-gamma, and interleukin-4 (IL-4) were determined by enzyme-linked immunosorbent assay. T cell proliferation response was determined by measuring the incorporation of (3)H-thymidine. Cytokine messenger RNA (mRNA) expression was detected in synovial tissues and peritoneal cells by real-time polymerase chain reaction. RESULTS: Arthritis severity was significantly reduced in PAR-1(-/-) mice compared with WT mice (P = 0.017). Analysis of individual aspects of joint histology revealed significant reductions in synovial exudates (P < 0.001), cartilage degradation (P < 0.01), and bone damage (P = 0.05) in PAR-1(-/-) mice. Synovial IL-1, IL-6, and matrix metalloproteinase 13 ( MMP-13) mRNA was significantly reduced in PAR-1(-/-) mice. The titers of antigen-specific serum anti-mBSA total IgG, IgG1, and IgG2a were significantly reduced, and serum IL-4 was significantly increased in arthritic PAR-1(-/-) mice. In contrast, no difference was observed in antigen-induced T cell proliferation between PAR-1(-/-) and WT mice. In vitro, thrombin-induced (but not lipopolysaccharide-induced) IL-1, IL-6, and MMP-13 mRNA expression was significantly impaired in PAR-1(-/-) mice compared with WT controls. CONCLUSION: These data demonstrate the requirement of PAR-1 for the expression of AIA, the development of an antigen-specific Ig response, thrombin-induced macrophage cytokine and MMP expression, and the inhibitory effect of PAR-1 on serum IL-4. We conclude that PAR-1 plays a significant role in this model of arthritis.[1]


  1. Reduction of arthritis severity in protease-activated receptor-deficient mice. Yang, Y.H., Hall, P., Little, C.B., Fosang, A.J., Milenkovski, G., Santos, L., Xue, J., Tipping, P., Morand, E.F. Arthritis Rheum. (2005) [Pubmed]
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