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Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with leukocyte adhesion to and extravasation through vascular endothelium into synovial tissue. Recent evidence indicates that the thrombospondin 1 gene is up‐regulated in patients with RA. We have identified a region within the TSP‐1 type 3 repeats that inhibits human neutrophil elastase (HNE) and binds to human neutrophils. The present study was undertaken to investigate the therapeutic benefit of this TSP‐1–derived peptide sequence and its effect on connective tissue growth factor (CTGF), a protein involved in fibrotic disorders and in neovascularization, which is a hallmark of RA.CTGF gene and protein expression, as well as protein levels of CTGF in the synovium, after treatment with the TSP‐1–derived peptide were studied in the peptidoglycan–polysaccharide animal model of erosive arthritis.Peptide treatment prevented joint infiltration and inflammation and was associated with reduced circulating antigen levels of HNE and TSP‐1. Additionally, CTGF was up‐regulated in this experimental model of RA. Treatment with the TSP‐1–derived peptide was associated with down‐regulation of the message and protein levels of CTGF. Immunofluorescence studies showed that the mean area fraction of CTGF immunoreactivity in the peptide‐treated group of animals was significantly less than that in the untreated group.These results document a role for TSP‐1 in regulating CTGF gene and protein expression in synovial tissue, suggesting a link with the disease course in this model of RA. This TSP‐1–derived synthetic peptide may represent an important template for drug development in RA and other inflammatory conditions associated with neutrophil activation. [ABSTRACT FROM AUTHOR]

To compare inflammatory peripheral arthritis in wild‐type and high molecular weight kininogen (HK)–deficient rats, both on the genetically susceptible Lewis background.By backcrossing Brown‐Norway HK‐deficient rats with Lewis rats for 6 generations, 2 new strains were produced, wild‐type F6 and HK‐deficient F6, each with a 98.5% Lewis genome. Inflammatory arthritis was induced by intraperitoneal injection of peptidoglycan–polysaccharide (PG‐PS), and the clinical, histopathologic, and biochemical responses were compared in both strains.Eighteen days after PG‐PS injection, rats with normal concentrations of HK showed weight loss and marked increase in hind ankle diameter with severe synovial inflammation and cartilage abnormalities. In contrast, HK‐deficient rats showed no weight loss (P < 0.05), no increase in hind ankle diameter (P < 0.05), and an absence of inflammatory changes (P < 0.05), as measured by the histologic and morphometric Mankin grading system for synovial and cartilage injury.Plasma HK is a key mediator of acute and chronic inflammatory arthritis in genetically susceptible Lewis rats. [ABSTRACT FROM AUTHOR]