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Down-regulation of connective tissue growth factor and type I collagen mRNA expression by connective tissue growth factor antisense oligonucleotide during experimental liver fibrosis

Authors

  • Kozue Uchio PhD,

    1. From the Groupe de Recherches pour l'Etude du Foiea, INSERM E0362, and Institut Fédératif de Recherche 66, Pathologies Infectieuses et Cancers, Université Victor Segalen Bordeaux 2, Bordeaux, France; Unit of Anatomy and Cell Biologyb, Department of Animal Sciences, Kyoto University, Kyoto, Japan; and ISIS Pharmaceuticalsc, Carlsbad, California.
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  • a,b Mark Graham PhD,

    1. From the Groupe de Recherches pour l'Etude du Foiea, INSERM E0362, and Institut Fédératif de Recherche 66, Pathologies Infectieuses et Cancers, Université Victor Segalen Bordeaux 2, Bordeaux, France; Unit of Anatomy and Cell Biologyb, Department of Animal Sciences, Kyoto University, Kyoto, Japan; and ISIS Pharmaceuticalsc, Carlsbad, California.
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  • c Nicholas M. Dean PhD,

    1. From the Groupe de Recherches pour l'Etude du Foiea, INSERM E0362, and Institut Fédératif de Recherche 66, Pathologies Infectieuses et Cancers, Université Victor Segalen Bordeaux 2, Bordeaux, France; Unit of Anatomy and Cell Biologyb, Department of Animal Sciences, Kyoto University, Kyoto, Japan; and ISIS Pharmaceuticalsc, Carlsbad, California.
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  • c Jean Rosenbaum MD, PhD,

    1. From the Groupe de Recherches pour l'Etude du Foiea, INSERM E0362, and Institut Fédératif de Recherche 66, Pathologies Infectieuses et Cancers, Université Victor Segalen Bordeaux 2, Bordeaux, France; Unit of Anatomy and Cell Biologyb, Department of Animal Sciences, Kyoto University, Kyoto, Japan; and ISIS Pharmaceuticalsc, Carlsbad, California.
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  • and a Alexis Desmoulière PhD a

    Corresponding author
    1. From the Groupe de Recherches pour l'Etude du Foiea, INSERM E0362, and Institut Fédératif de Recherche 66, Pathologies Infectieuses et Cancers, Université Victor Segalen Bordeaux 2, Bordeaux, France; Unit of Anatomy and Cell Biologyb, Department of Animal Sciences, Kyoto University, Kyoto, Japan; and ISIS Pharmaceuticalsc, Carlsbad, California.
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Dr. Alexis Desmoulière, GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, 146, rue Léo-Saignat, 33076 Bordeaux cedex, France. Fax: +33 556 51 40 77; Email: Alexis.Desmouliere@gref.u-bordeaux2.fr.

Abstract

Transforming growth factor (TGF)-β1 is a major mediator of liver fibrosis. Connective tissue growth factor (CTGF) mediates TGF-β1 pro-fibrogenic effects in vitro, but its in vivo role is unknown. Both TGF-β1 and CTGF are overexpressed in hepatic stellate cells during liver fibrosis. We have used antisense oligonucleotides to examine the role of CTGF in carbon tetrachloride-induced liver fibrosis in mice. Mice received carbon tetrachloride together with CTGF or TGF-β1 antisense oligonucleotides for 2 weeks (preventive model), or carbon tetrachloride for 2 weeks followed by carbon tetrachloride and oligonucleotides for 2 more weeks (curative model). In both models, CTGF and TGF-β1 oligonucleotides decreased by more than 50 percent the mRNA expression of their targets. Type I collagen mRNA was also decreased by about 40 percent in the preventive experiment. Tissue inhibitor of matrix metalloproteinase-1 mRNA expression and fibrotic deposition evaluated by Sirius red staining were not modified in any group. In summary, our results suggest that hepatic stellate cells can be targeted in vivo with oligonucleotides, and that reducing CTGF levels can lead to a decrease in fibrogenesis as shown by the reduction in type I collagen expression. The lack of effect on fibrosis may be due to the persistence of high tissue inhibitor of matrix metalloproteinase-1 expression.

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