Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice

P. Czochra, Borut Klopcic, E. Meyer, J. Herkel, J.F. Garcia-Lazaro, F. Thieringer, P. Schirmacher, S. Biesterfeld, P.R. Galle, A.W. Lohse, S. Kanzler

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    Abstract

    Background/Aims: In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice.Methods: Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/IoxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured.Results: PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-beta expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4-6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-beta expression was unchanged.Conclusions: We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta 1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
    Original languageEnglish
    Pages (from-to)419-428
    JournalJournal of Hepatology
    Volume45
    Issue number3
    DOIs
    Publication statusPublished - 2006

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    Liver Cirrhosis
    Transgenic Mice
    Hepatic Stellate Cells
    Matrix Metalloproteinases
    Transforming Growth Factor beta
    Breeding
    Actins
    Liver
    Cell Transdifferentiation
    Platelet-Derived Growth Factor beta Receptor
    Transforming Growth Factor beta1
    Tissue Inhibitor of Metalloproteinase-1
    Myofibroblasts
    Tamoxifen
    Helper-Inducer T-Lymphocytes
    Extracellular Matrix
    Smooth Muscle
    Albumins
    Fibrosis
    Collagen

    Cite this

    Czochra, P., Klopcic, B., Meyer, E., Herkel, J., Garcia-Lazaro, J. F., Thieringer, F., ... Kanzler, S. (2006). Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. Journal of Hepatology, 45(3), 419-428. https://doi.org/10.1016/j.jhep.2006.04.010
    Czochra, P. ; Klopcic, Borut ; Meyer, E. ; Herkel, J. ; Garcia-Lazaro, J.F. ; Thieringer, F. ; Schirmacher, P. ; Biesterfeld, S. ; Galle, P.R. ; Lohse, A.W. ; Kanzler, S. / Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. In: Journal of Hepatology. 2006 ; Vol. 45, No. 3. pp. 419-428.
    @article{252ad669965e442abca1f7e68b3cdc13,
    title = "Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice",
    abstract = "Background/Aims: In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice.Methods: Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/IoxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured.Results: PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-beta expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4-6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-beta expression was unchanged.Conclusions: We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta 1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.",
    author = "P. Czochra and Borut Klopcic and E. Meyer and J. Herkel and J.F. Garcia-Lazaro and F. Thieringer and P. Schirmacher and S. Biesterfeld and P.R. Galle and A.W. Lohse and S. Kanzler",
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    Czochra, P, Klopcic, B, Meyer, E, Herkel, J, Garcia-Lazaro, JF, Thieringer, F, Schirmacher, P, Biesterfeld, S, Galle, PR, Lohse, AW & Kanzler, S 2006, 'Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice' Journal of Hepatology, vol. 45, no. 3, pp. 419-428. https://doi.org/10.1016/j.jhep.2006.04.010

    Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. / Czochra, P.; Klopcic, Borut; Meyer, E.; Herkel, J.; Garcia-Lazaro, J.F.; Thieringer, F.; Schirmacher, P.; Biesterfeld, S.; Galle, P.R.; Lohse, A.W.; Kanzler, S.

    In: Journal of Hepatology, Vol. 45, No. 3, 2006, p. 419-428.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice

    AU - Czochra, P.

    AU - Klopcic, Borut

    AU - Meyer, E.

    AU - Herkel, J.

    AU - Garcia-Lazaro, J.F.

    AU - Thieringer, F.

    AU - Schirmacher, P.

    AU - Biesterfeld, S.

    AU - Galle, P.R.

    AU - Lohse, A.W.

    AU - Kanzler, S.

    PY - 2006

    Y1 - 2006

    N2 - Background/Aims: In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice.Methods: Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/IoxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured.Results: PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-beta expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4-6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-beta expression was unchanged.Conclusions: We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta 1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

    AB - Background/Aims: In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice.Methods: Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/IoxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured.Results: PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-beta expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4-6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-beta expression was unchanged.Conclusions: We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta 1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

    U2 - 10.1016/j.jhep.2006.04.010

    DO - 10.1016/j.jhep.2006.04.010

    M3 - Article

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    SP - 419

    EP - 428

    JO - Journal of Hepatology

    JF - Journal of Hepatology

    SN - 0168-8278

    IS - 3

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    Czochra P, Klopcic B, Meyer E, Herkel J, Garcia-Lazaro JF, Thieringer F et al. Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. Journal of Hepatology. 2006;45(3):419-428. https://doi.org/10.1016/j.jhep.2006.04.010