Abstract
The angiogenic factor VEGF promotes synovitis and bone erosion in rheumatoid arthritis (RA). Previously, we have demonstrated that VEGF expression correlates with disease severity in RA patients and in murine collagen-induced arthritis (CIA). In this study, we adopted an adenoviral gene delivery system expressing soluble VEGF receptor 1 (sFlt-1) to further study the role of VEGF in CIA. Arthritis was induced in DBA/1 mice by injection of bovine collagen. Adenoviruses expressing human soluble VEGF receptor 1 (AdvsFlt-1), or without transgene (Adv0), were injected intravenously on the first day of arthritis. We found that disease severity and paw swelling were significantly suppressed in mice receiving AdvsFlt-1, when compared to untreated or Adv0-treated mice. Expression of sFlt-1 peaked 24 h after injection, with protein detectable in the liver, synovial issue and serum, but rapidly decreased by 72 h. The effect of sFlt-1 expression on signs of disease was paralleled by reduced joint destruction and decreased expression of the vascular marker von Willebrand factor. In summary, adenoviral delivery of human soluble VEGF receptor type 1 significantly suppressed disease activity in CIA. The actions of AdvsFlt-1 are likely to be mediated by reduced synovial neovascularization, and these results support the concept that VEGF blockade may be an effective therapeutic adjunct for the treatment of RA.
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Acknowledgements
We thank Professor Ronald Crystal (Weill Medical College of Cornell University, New York, NY, USA) for his generous gift of the adenovirus expressing human soluble VEGF receptor sFlt-1. The Kennedy Institute of Rheumatology Division receives a Core Grant from arc (Registered Charity No. 207711). Dr A Afuwape was partly funded by the Nuffield Foundation (The Oliver Bird Fund for Rheumatism and Arthritis Research) and EU framework programme 5 (QLG1-CT-2001-01407). We are grateful to Paul Warden and the staff of the Biological Services Unit for the care and maintenance of animals.
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Afuwape, A., Feldmann, M. & Paleolog, E. Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis. Gene Ther 10, 1950–1960 (2003). https://doi.org/10.1038/sj.gt.3302104
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DOI: https://doi.org/10.1038/sj.gt.3302104
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