Gene transfer of a fibronectin peptide inhibits leukocyte recruitment and suppresses inflammation in mouse collagen-induced arthritis.
OBJECTIVE
Cell adhesion plays an essential role in arthritis by recruiting and retaining leukocytes in the joint. Fibronectin, a major extracellular matrix component in synovium, plays a central role in cell-cell and cell-matrix interactions through ligation of cell surface integrins. The present study was designed to determine the effects of gene transfer of a 15-amino acid peptide derived from the 33-kd carboxy-terminal cell and heparin-binding domain of fibronectin (FN-C/H-II) on established arthritis in mice.


METHODS
Plasmid DNA encoding a FN-C/H-II minigene under control of the cytomegalovirus promoter was injected intravenously into mice with established collagen-induced arthritis, and the effects on leukocyte adhesion and recruitment to the joints was determined.


RESULTS
Following injection, circulating FN-C/H-II could be detected for at least 5 days. Treated mice demonstrated a marked reduction in progression of arthritis. Not only was disease progression halted, but a significant improvement in joint swelling was observed within 2 days of treatment. Leukocyte adhesion and recruitment were inhibited by FN-C/H-II, both in vitro and in vivo. Histologic evaluation revealed a marked reduction in infiltration of both neutrophils and lymphocytes into synovium, persisting for at least 10 days.


CONCLUSIONS
These results suggest that antagonism of cell adhesion by soluble fibronectin peptides may provide an approach to attenuating chronic arthritis.
Imagawa
Tomoyuki
T
Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Watanabe
Shohei
S
Katakura
Shigeki
S
Boivin
Gregory P
GP
Hirsch
Raphael
R
D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D002448:Cell Adhesion / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D005353:Fibronectins / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D066298:In Vitro Techniques; D007596:Joints / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000166:cytology* / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D010957:Plasmids; D019076:Transgenes / Q000276:immunology
D005353:Fibronectins