A peptide from thrombospondin 1 modulates experimental erosive arthritis by regulating connective tissue growth factor.
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.


CONCLUSIONS
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.
Manns
Joanne M
JM
Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. mannsjm@temple.edu
Uknis
Audrey B
AB
Rico
Mario C
MC
Agelan
Alexis
A
Castaneda
Julian
J
Arango
Israel
I
Barbe
Mary F
MF
Safadi
Fayez F
FF
Popoff
Steven N
SN
DeLa Cadena
Raul A
RA
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055513:Connective Tissue Growth Factor; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006614:Hindlimb; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007596:Joints / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019700:Thrombospondin 1 / Q000737:chemistry
C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D012333:RNA, Messenger; D019700:Thrombospondin 1; D055513:Connective Tissue Growth Factor