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. CONCLUSION: These results suggest that antagonism of cell adhesion by soluble fibronectin peptides may provide an approach to attenuating chronic arthritis.