Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes.
OBJECTIVE
Mdr2 (Abcb4)-/- mice develop hepatic lesions resembling primary sclerosing cholangitis. Our aim was to characterize the evolution of fibrosis in Mdr2-/- mice.


METHODS
Mdr2-/-mice and their wild-type littermates were sacrificed at 2, 4 and 8 weeks after birth. Hepatic collagen was determined biochemically. Fibrosis related transcript levels were quantified from livers by real-time RT-PCR, and MMP activities determined by substrate assays. Liver histology was assessed by connective tissue staining and immunohistochemistry for alpha-smooth muscle actin (alpha-SMA).


RESULTS
Mdr2-/- mice demonstrated a time-dependent increase of relative and total hepatic collagen (fivefold at 8 weeks, compared to wildtype controls), and maximal alpha-SMA immunoreactivity at 4 weeks. Compared to wildtype controls profibrogenic mRNA levels for procollagen alpha1(I), TGFbeta1, TGFbeta2, MMP-2 and -13, TIMP-1, PDGFbeta receptor, and PAI-1 were upregulated up to 27-fold. Most transcripts peaked at 4 weeks, but procollagen alpha1(I) mRNA increased steadily, TIMP-1 mRNA was constantly elevated (20-fold), MMP-13 mRNA was suppressed and interstitial collagenase and gelatinase activities were downregulated.


CONCLUSIONS
Mdr2-/- mice spontaneously progress to severe biliary fibrosis. This is due to a characteristic temporal pattern of upregulated profibrogenic and downregulated fibrolytic genes and activities. These mice are an attractive model to test potential antifibrotics for the treatment of (biliary) liver fibrosis.
Popov
Yury
Y
Laboratory of Liver Research, Department of Medicine I, University of Erlangen-Nuremberg, Germany; Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Patsenker
Eleonora
E
Fickert
Peter
P
Trauner
Michael
M
Schuppan
Detlef
D
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D004195:Disease Models, Animal; D008103:Liver Cirrhosis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000097202:ATP-Binding Cassette Sub-Family B Member 4