Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice.
OBJECTIVE
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.
Czochra
Piotr
P
Department of Medicine, Johannes Gutenberg-University, Mainz, Germany.
Klopcic
Borut
B
Meyer
Erik
E
Herkel
Johannes
J
Garcia-Lazaro
Jose Francisco
JF
Thieringer
Florian
F
Schirmacher
Peter
P
Biesterfeld
Stefan
S
Galle
Peter R
PR
Lohse
Ansgar W
AW
Kanzler
Stephan
S
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; C045073:Cre recombinase; D019426:Integrases