title: 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.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Onozuka
authors.forename: Sei
authors.initials: S
authors.lastname: Kakinuma
authors.forename: Akihide
authors.initials: A
authors.lastname: Kamiya
authors.forename: Masato
authors.initials: M
authors.lastname: Miyoshi
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Kei
authors.initials: K
authors.lastname: Kiyohashi
authors.forename: Takako
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Funaoka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ueyama
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Naohiko
authors.initials: N
authors.lastname: Koshikawa
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002779:Cholestasis / Q000150:complications*; D024042:Collagen Type I / Q000378:metabolism; D018450:Disease Progression; D008103:Liver Cirrhosis / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D024042:Collagen Type I; D019715:Tissue Inhibitor of Metalloproteinase-1; D002251:Carbon Tetrachloride; D020778:Matrix Metalloproteinase 2