Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice.

Abstract

Matrix metalloproteinase (MMP) plays an important role in homeostatic regulation of the extracellular environment and degradation of matrix. During liver fibrosis, several MMPs, including MMP-2, are up-regulated in activated hepatic stellate cells, which are responsible for exacerbation of liver cirrhosis. However, it remains unclear how loss of MMP-2 influences molecular dynamics associated with fibrogenesis in the liver. To explore the role of MMP-2 in hepatic fibrogenesis, we employed two fibrosis models in mice; toxin (carbon tetrachloride, CCl4)-induced and cholestasis-induced fibrosis. In the chronic CCl4 administration model, MMP-2 deficient mice exhibited extensive liver fibrosis as compared with wild-type mice. Several molecules related to activation of hepatic stellate cells were up-regulated in MMP-2 deficient liver, suggesting that myofibroblastic change of hepatic stellate cells was promoted in MMP-2 deficient liver. In the cholestasis model, fibrosis in MMP-2 deficient liver was also accelerated as compared with wild type liver. Production of tissue inhibitor of metalloproteinase 1 increased in MMP-2 deficient liver in both models, while transforming growth factor β, platelet-derived growth factor receptor and MMP-14 were up-regulated only in the CCl4 model. Our study demonstrated, using 2 experimental murine models, that loss of MMP-2 exacerbates liver fibrosis, and suggested that MMP-2 suppresses tissue inhibitor of metalloproteinase 1 up-regulation during liver fibrosis.

• Authors: Izumi Onozuka, Sei Kakinuma, Akihide Kamiya, Masato Miyoshi, Naoya Sakamoto, Kei Kiyohashi, Takako Watanabe, Yusuke Funaoka, Mayumi Ueyama, Mina Nakagawa, Naohiko Koshikawa, Motoharu Seiki, Hiromitsu Nakauchi, Mamoru Watanabe
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 406 Issue 1 Pg. 134-40 (Mar 04 2011) ISSN: 1090-2104 [Electronic] United States
• PMID: 21300023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Acta2 protein, mouse
• Actins
• Collagen Type I
• Tissue Inhibitor of Metalloproteinase-1
• Carbon Tetrachloride
• Matrix Metalloproteinase 2

Topics

• Actins (metabolism)
• Animals
• Carbon Tetrachloride (toxicity)
• Cholestasis (complications)
• Collagen Type I (metabolism)
• Disease Progression
• Liver Cirrhosis (enzymology, etiology, pathology)
• Matrix Metalloproteinase 2 (genetics, physiology)
• Mice
• Mice, Knockout
• Tissue Inhibitor of Metalloproteinase-1 (metabolism)