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.
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.
Authors: Mario C Rico; James J Rough; Joanne M Manns; Fabiola Del Carpio-Cano; Fayez F Safadi; Satya P Kunapuli; Raul A DeLa Cadena Journal: Thromb Res Date: 2011-09-01 Impact factor: 3.944
Authors: Michael E Ezzie; Melissa G Piper; Christine Montague; Christie A Newland; Judy M Opalek; Chris Baran; Naeem Ali; David Brigstock; Jack Lawler; Clay B Marsh Journal: Am J Respir Cell Mol Biol Date: 2010-06-25 Impact factor: 6.914
Authors: Mario C Rico; Joanne M Manns; Jeffrey B Driban; Audrey B Uknis; Satya P Kunapuli; Raul A Dela Cadena Journal: Transl Res Date: 2008-07-11 Impact factor: 7.012
Authors: Jennifer A Jones; Mark R Gray; Beatriz Enes Oliveira; Manuel Koch; John J Castellot Journal: J Cell Commun Signal Date: 2007-11-20 Impact factor: 5.782
Authors: Helen G L Gao; Paul W Fisher; Alex G Lambi; Christine K Wade; Ann E Barr-Gillespie; Steven N Popoff; Mary F Barbe Journal: PLoS One Date: 2013-08-28 Impact factor: 3.240