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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.

Abstract
Transforming growth factor (TGF)-beta 1 is a major mediator of liver fibrosis. Connective tissue growth factor (CTGF) mediates TGF-beta 1 pro-fibrogenic effects in vitro, but its in vivo role is unknown. Both TGF-beta 1 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-beta 1 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-beta 1 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.
AuthorsKozue Uchio, Mark Graham, Nicholas M Dean, Jean Rosenbaum, Alexis Desmoulière
JournalWound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society (Wound Repair Regen) 2004 Jan-Feb Vol. 12 Issue 1 Pg. 60-6 ISSN: 1067-1927 [Print] United States
PMID14974966 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CCN2 protein, mouse
  • Collagen Type I
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Carbon Tetrachloride
Topics
  • Animals
  • Carbon Tetrachloride (adverse effects)
  • Collagen Type I (biosynthesis, genetics)
  • Connective Tissue Growth Factor
  • Down-Regulation (genetics)
  • Gene Expression (genetics)
  • Immediate-Early Proteins (biosynthesis, genetics)
  • Intercellular Signaling Peptides and Proteins (biosynthesis, genetics)
  • Liver Cirrhosis (chemically induced, therapy)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Animal
  • Oligonucleotides, Antisense (genetics)
  • RNA, Messenger (genetics)
  • Transforming Growth Factor beta (biosynthesis, genetics)
  • Transforming Growth Factor beta1

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