title: TIMP-1 is upregulated, but not essential in hepatic fibrogenesis and carcinogenesis in mice.
abstract: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is upregulated during hepatic fibrogenesis and considered to promote fibrosis in the injured liver by inhibition of matrix metalloproteases (MMP) and degradation of extracellular matrix. Moreover, TIMP-1 displays anti-apoptotic properties, in patients with hepatocellular carcinoma (HCC) TIMP-1 serum levels are elevated and high TIMP-1 expression levels in HCC are associated with a poor prognosis. Therefore, TIMP-1 could functionally link fibrogenesis and carcinogenesis in the liver. The aim of our study was to characterize the role of TIMP-1 in hepatic fibrogenesis and carcinogenesis. Experimental hepatic fibrogenesis as well as diethylnitrosamine (DEN) -induced hepatocarcinogenesis were studied in TIMP-1-deficient mice and wild type littermates. Hepatic TIMP-1 expression was upregulated following induction of liver fibrosis by bile duct ligation (BDL) or by carbon tetrachloride (CCl4). Unexpectedly, in comparison to wild type littermates, TIMP-1-deficient mice were not protected from liver fibrosis induced by BDL or CCl4. TIMP-1 expression was significantly higher in HCC nodules than in surrounding liver tissue. However, experimental hepatic carcinogenesis was similar in TIMP-1-deficient mice and wild type littermates following DEN-treatment or combined treatment with DEN and CCl4. Therefore we concluded that TIMP-1 is not essential for hepatic fibrogenesis and carcinogenesis in mice.
authors.affiliation: Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nina D
authors.initials: ND
authors.lastname: Thiele
authors.affiliation: Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Wirth
authors.affiliation: Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Steins
authors.affiliation: Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Anja C
authors.initials: AC
authors.lastname: Koop
authors.affiliation: Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Ittrich
authors.affiliation: Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. j.kluwe@uke.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kluwe
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000378:metabolism; D008103:Liver Cirrhosis / Q000000981:diagnostic imaging / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008111:Liver Function Tests; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D019715:Tissue Inhibitor of Metalloproteinase-1