Open AccessA peptide from thrombospondin 1 modulates experimental erosive arthritis by regulating connective tissue growth factor
Author(s) -
Manns Joanne M.,
Uknis Audrey B.,
Rico Mario C.,
Agelan Alexis,
Castaneda Julian,
Arango Israel,
Barbe Mary F.,
Safadi Fayez F.,
Popoff Steven N.,
DeLa Cadena Raul A.
Publication year - 2006
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.22021
Subject(s) - ctgf , connective tissue , matricellular protein , thrombospondin , arthritis , growth factor , immunology , fibrosis , inflammation , thrombospondin 1 , rheumatoid arthritis , medicine , pathology , angiogenesis , biology , extracellular matrix , microbiology and biotechnology , metalloproteinase , matrix metalloproteinase , receptor
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.