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/loxP 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-beta1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo.
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/loxP 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-beta1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo.
Authors: Andreas Teufel; Diana Becker; Susanne N Weber; Steven Dooley; Katja Breitkopf-Heinlein; Thorsten Maass; Katrin Hochrath; Markus Krupp; Jens U Marquardt; Martin Kolb; Bernhard Korn; Christof Niehrs; Tim Zimmermann; Patricio Godoy; Peter R Galle; Frank Lammert Journal: J Mol Med (Berl) Date: 2012-06-06 Impact factor: 4.599
Authors: Summer M Raines; Oliver C Richards; Lindsay R Schneider; Kathryn L Schueler; Mary E Rabaglia; Angie T Oler; Donald S Stapleton; Guillem Genové; John A Dawson; Christer Betsholtz; Alan D Attie Journal: Am J Physiol Endocrinol Metab Date: 2011-06-14 Impact factor: 4.310
Authors: Melissa A Linden; Ryan D Sheldon; Grace M Meers; Laura C Ortinau; E Matthew Morris; Frank W Booth; Jill A Kanaley; Victoria J Vieira-Potter; James R Sowers; Jamal A Ibdah; John P Thyfault; M Harold Laughlin; R Scott Rector Journal: J Physiol Date: 2016-05-27 Impact factor: 5.182