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Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis

Gene Therapy volume 9, pages 192–200 (2002)Cite this article

Abstract

Plasmin is essential for metalloproteases activation, endothelial cell migration and degradation of the extracellular matrix. The process is common to neoangiogenesis pannus formation and cartilage degradation within arthritic joints. Since 80% of synovial cells express urokinase plasminogen activator receptor (uPAR), we investigated the inhibition of plasmin activation in a collagen-induced arthritis (CIA) mice model, by expressing a uPA/uPAR antagonist molecule (ATF) fused to human serum albumin (HSA) to extend its serum half-life. Overexpression was obtained with an adenoviral vector expressing the chimeric murine ATF-HSA. We showed that the genetic coupling did not significantly reduce the ability of the ATF moiety to interact with its receptor uPAR. The chimeric protein was detectable in the sera of injected mice 7 days following Ad-mATF-HSA injection, then decreased in parallel with the anti-HSA titer increase. Systemic Ad-mATF-HSA injection performed on day 25 following CIA induction decreased the incidence of arthritis and the severity of the disease. Moreover, synovial angiogenesis in arthritic paws was decreased after Ad-mATF-HSA gene transfer, as assessed by smooth muscle actin immunostaining. The preventive effect observed on arthritis was related to the decrease in angiogenesis, rather than inhibition of extracellular matrix degradation.

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Acknowledgements

We would like to thank Michèle Radal from the CRLC Val d'Aurelle in Montpellier for the preparation of histology sections, and the breast radiography group from Lapeyronie Hospital in Montpellier who performed the X-rays. We also acknowledge Elisabeth Connault from UMR1582/CNRS-IGR for performing immunohistogical technical support.

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  1. F Apparailly and C Bouquet: The first two authors contributed equally to this work

Authors and Affiliations

  1. INSERM U475, Montpellier, France

    F Apparailly, V Millet, D Noel, C Jacquet, J Sany & C Jorgensen

  2. Service d'Immuno-Rhumatologie, Hôpital Lapeyronie, Montpellier, France

    J Sany & C Jorgensen

  3. Institut Gustave Roussy UMR1582/Centre National de la Recherche Scientifique Gencell-Aventis, Villejuif, France

    C Bouquet, P Opolon, M Perricaudet & P Yeh

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  1. F Apparailly
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Apparailly, F., Bouquet, C., Millet, V. et al. Adenovirus-mediated gene transfer of urokinase plasminogen inhibitor inhibits angiogenesis in experimental arthritis. Gene Ther 9, 192–200 (2002). https://doi.org/10.1038/sj.gt.3301628

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  • DOI: https://doi.org/10.1038/sj.gt.3301628

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