A peptide from thrombospondin 1 modulates experimental erosive arthritis by regulating connective tissue growth factor.
Manns-JM; Uknis-AB; Rico-MC; Agelan-A; Castaneda-J; Arango-I; Barbe-MF; Safadi-FF; Popoff-SN; DeLa Cadena-RA
Arthritis Rheum 2006 Aug; 54(8):2415-2422
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.
Peptides; Diseases; Genes; Proteins; Models; Animals; Animal-studies; Antigens
Joanne M. Manns, Temple University School of Medicine, Department of Physiology 230 B OMS, 3400 North Broad Street, Philadelphia, PA 19140
Arthritis and Rheumatism