Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice |
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Authors: | Onozuka Izumi Kakinuma Sei Kamiya Akihide Miyoshi Masato Sakamoto Naoya Kiyohashi Kei Watanabe Takako Funaoka Yusuke Ueyama Mayumi Nakagawa Mina Koshikawa Naohiko Seiki Motoharu Nakauchi Hiromitsu Watanabe Mamoru |
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Institution: | aDepartment of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan;bDepartment for Hepatitis Control, Tokyo Medical and Dental University, Japan;cDivision of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Japan;dSchool of Medicine, Tokyo Medical and Dental University, Japan;eDivision of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Japan |
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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. |
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Keywords: | Bile duct ligation Carbon tetrachloride PDGF receptor TIMP1 TGFβ |
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