Suppression of murine collagen-induced arthritis by targeted apoptosis of synovial neovasculature.
Because angiogenesis plays a major role in the perpetuation of inflammatory arthritis, we explored a method for selectively targeting and destroying new synovial blood vessels. Mice with collagen-induced arthritis were injected intravenously with phage expressing an RGD motif. In addition, the RGD peptide (RGD-4C) was covalently linked to a proapoptotic heptapeptide dimer, D(KLAKLAK)2, and was systemically administered to mice with collagen-induced arthritis. A phage displaying an RGD-containing cyclic peptide (RGD-4C) that binds selectively to the alpha(v)beta3 and alpha(v)beta5 integrins accumulated in inflamed synovium but not in normal synovium. Homing of RGD-4C phage to inflamed synovium was inhibited by co-administration of soluble RGD-4C. Intravenous injections of the RGD-4C-D(KLAKLAK)2 chimeric peptide significantly decreased clinical arthritis and increased apoptosis of synovial blood vessels, whereas treatment with vehicle or uncoupled mixture of the RGD-4C and the untargeted proapoptotic peptide had no effect. Targeted apoptosis of synovial neovasculature can induce apoptosis and suppress clinical arthritis. This form of therapy has potential utility in the treatment of inflammatory arthritis.
Gerlag
D M
DM
Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
Borges
E
E
Tak
P P
PP
Ellerby
H M
HM
Bredesen
D E
DE
Pasqualini
R
R
Ruoslahti
E
E
Firestein
G S
GS
D000818:Animals; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017104:Bacteriophage M13 / Q000235:genetics; D001667:Binding, Competitive; D003094:Collagen; D016503:Drug Delivery Systems / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D020287:In Situ Nick-End Labeling; D016023:Integrins / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy*; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D019030:Receptors, Vitronectin / Q000378:metabolism; D013583:Synovial Membrane / Q000098:blood supply* / Q000276:immunology
D016023:Integrins; D009842:Oligopeptides; D010446:Peptide Fragments; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C047981:arginyl-glycyl-aspartic acid; D003094:Collagen