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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
Author(s) -
Uchio Kozue,
Graham Mark,
Dean Nicholas M.,
Rosenbaum Jean,
Desmoulière Alexis
Publication year - 2004
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/j.1067-1927.2004.012112.x-1
Subject(s) - ctgf , connective tissue , hepatic stellate cell , sirius red , growth factor , fibrosis , transforming growth factor , collagen, type i, alpha 1 , chemistry , carbon tetrachloride , biology , cancer research , microbiology and biotechnology , endocrinology , pathology , medicine , extracellular matrix , biochemistry , receptor , organic chemistry
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.