Matrix Metalloproteinase-13 Promotes Recovery from Experimental Liver Cirrhosis in Rats

• Published in: Pathobiology (Basel) Vol. 78; no. 5; pp. 239 - 252
• Main Authors: Endo, Hitoshi, Niioka, Maki, Sugioka, Yoshihiko, Itoh, Johbu, Kameyama, Kaori, Okazaki, Isao, Ala-Aho, Risto, Kähäri, Veli-Matti, Watanabe, Tetsu
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2011
• Subjects: Animals; Blotting, Western; Gene Expression Regulation, Enzymologic; Hepatocyte Growth Factor - metabolism; Humans; Immunohistochemistry; Liver cirrhosis; Liver Cirrhosis, Experimental - genetics; Liver Cirrhosis, Experimental - metabolism; Male; Matrix; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 13 - metabolism; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Original Paper; Proteins; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Transfection; Matrix metalloproteinase(s); Extracellular matrix; Hepatocyte growth factor; Interstitial collagenase; Fibrosis; Adenoviral gene transfer
• ISSN: 1015-2008; 1423-0291
• DOI: 10.1159/000328841

Objective: To evaluate the role of matrix metalloproteinase (MMP)-13 gene expression in the early phase of recovery from liver fibrosis/cirrhosis. Methods: Liver fibrosis was induced in male Wistar rats by administration of carbon tetrachloride (CCl 4 ) for 10 weeks. Recombinant adenovirus-mediated human MMP-13 gene transfer (RAdMMP-13) was performed via the femoral vein on day 3 after the last CCl 4 injection. The role of MMP-13 in stably expressing cell lines was also analyzed. Results: Fibrous deposition in the liver was decreased in RAdMMP-13-injected rats by day 3 after gene transfer compared with empty vector RAd66-injected rats. Furthermore, MMP-2 and MMP-9 enzymatic activity was markedly enhanced in the liver of RAdMMP-13 injected rats. Hepatocyte growth factor (HGF) induction was also increased in RAdMMP-13 injected rats. In established stable HT-1080 cells transfected with MMP-13, HGF-α expression and MMP-2 and MMP-9 enzymatic activity were increased. The conversion of precursor HGF into mature HGF was also increased in the MMP-13 expressing cell lines. Conclusion: Forced MMP-13 expression effectively accelerated recovery from liver cirrhosis via the effects of MMP-13-mediated HGF, MMP-2, and MMP-9 expression, which induced the degradation of collagen fibers and promoted hepatic regeneration.