SYNTHETIC FIBRONECTIN PEPTIDES SUPPRESS ARTHRITIS IN RATS BY INTERRUPTING LEUKOCYTE ADHESION AND RECRUITMENT

In an experimental model of arthritis, increased leukocyte adhesion is associated with the evolution of acute and chronic synovial inflammat ion. Whereas peripheral blood mononuclear cells (PBMC) from control an imals bind minimally to fibronectin matrices, PBMC from animals receiv ing arthropathic doses of bacterial cell walls demonstrate increased i ntegrin mRNA expression and enhanced adhesion. To determine whether th is augmented adhesion was causal in the development of synovial pathol ogy, peptides synthesized from several fibronectin domains which inhib ited leukocyte adhesion in vitro were administered to arthritic animal s either as free peptides or coupled to a carrier molecule. Not only w ere peptides containing either the RGD or CS-1 cell-binding domains in hibitory to chronic synovial pathology (articular index = 10.5 +/- 0.3 for untreated animals compared to 1.25 +/- 0.25 for RGD and 2.5 +/- 0 .7 for CS-1), but three peptides synthesized from the carboxy-terminal 33- kD heparin-binding domain of fibronectin were also found to signi ficantly inhibit leukocyte recruitment and the evolution of arthritis. Based on these data, which are the first to explore the therapeutic p otential of heparin-binding fibronectin peptides in chronic inflammati on, it appears that antagonism of cellular adhesion and recruitment by fibronectin peptides may provide an important mechanism for modulatin g the multi-step adhesion process and attenuating aberrant inflammator y responses.