Sm. Wahl et al., SYNTHETIC FIBRONECTIN PEPTIDES SUPPRESS ARTHRITIS IN RATS BY INTERRUPTING LEUKOCYTE ADHESION AND RECRUITMENT, The Journal of clinical investigation, 94(2), 1994, pp. 655-662
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.