No abstract

Objective. 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.Methods. 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.Results. 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.Conclusion. 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.

Both inflammation and angiogenesis were decreased after TSP1-derived peptide treatment indicating a potential pathway by which TSP1 interaction with neutrophils induces CTGF in RA affected tissues.

We investigate whether the previously shown contact system activation plays a pathogenetic role in a rat model of acute inflammation induced by peptidoglycan‐polysaccharide (PG‐APS) using a new specific plasma kallikrein inhibitor, Bz‐Pro‐Phe‐boroArg‐OH (P8720). Group I (control) received neither PG‐APS nor inhibitor. Group II (disease‐treated) received PG‐APS intraperitoneally (IP) and P8720 orally. Group III (disease‐untreated) received PG‐APS IP. Anemia was evident at 49 h in group III but was not present (P < 0.01) in groups I and II. Spleen weight was significantly decreased in group II compared to group III. Acute arthritis progressively developed in group III from 27 to 49 h, but P8720 decreased the joint swelling in group II by 61% (P < 0.0005). We observed a significant fall in prekallikrein and factor XI (P < 0.01) in groups II and III but not in group I. The decrease in the functional levels of high molecular weight kininogen (P < 0.05) observed in group III were prevented by P8720 in group II. The changes in T‐kininogen and α1‐inhibitor 3 acute‐phase proteins were partially prevented by P8720. We conclude that the inflammatory reactions leading to arthritis and anemia, as well as the acute‐phase reaction, are due in part to contact activation, and that specific kallikrein inhibitors may have therapeutic potential.—DeLa Cadena, R. A., Stadnicki, A., Uknis, A. B., Sartor, R. B., Kettner, C. A., Adam, A., Colman, R. W. Inhibition of plasma kallikrein prevents peptidoglycan‐induced arthritis in the Lewis rat. FASEB J. 9, 446–452 (1995)