Suppression of murine collagen-induced arthritis by targeted apoptosis of synovial neovasculature |
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| Authors: | Danielle M Gerlag Eric Borges Paul P Tak H Michael Ellerby Dale E Bredesen Renata Pasqualini Erkki Ruoslahti Gary S Firestein |
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| Institution: | (1) Division of Rheumatology, Allergy and Immunology, San Diego School of Medicine, University of California, La Jolla, CA, USA;(2) The Burnham Institute, La Jolla, CA, USA;(3) Division of Clinical Immunology and Rheumatology, Academical Medical Center, University of Amsterdam, Amsterdam, The Netherlands;(4) MorphoSys AG, Martinsried, Munchen, Germany;(5) The Buck Center for Research in Aging, Novato, CA, USA;(6) Department of GU Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; |
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| Abstract: | 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 αvβ3 and αvβ5 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. |
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