A new Mdr2(-/-) mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer

Am J Pathol. 2015 Feb;185(2):325-34. doi: 10.1016/j.ajpath.2014.10.013. Epub 2014 Dec 2.


We previously characterized the Mdr2(Abcb4)(-/-) mouse as a reproducible model of chronic biliary liver disease. However, it demonstrates relatively slow fibrosis progression, possibly due to its fibrosis-resistant genetic background. We aimed to improve the model by moving it onto a fibrosis-susceptible background. We generated novel BALB/c.Mdr2(-/-) mouse via genetic backcross onto highly fibrosis-susceptible BALB/c substrain, identified in inbred mouse strain screening. Liver fibrosis, portal pressure, and hepatic tumor burden in BALB/c.Mdr2(-/-) mice were studied up to 1 year of age in direct comparison to parental strain FVB.Mdr2(-/-). BALB/c.Mdr2(-/-) mice developed periductular onion-skin type fibrotic lesions and pronounced ductular reaction starting from 4 weeks of age. Compared to parental strain, BALB/c.Mdr2(-/-) mice demonstrated dramatically accelerated liver fibrosis, with threefold increase in collagen deposition and bridging fibrosis/early signs of cirrhosis at 12 weeks. This was accompanied by early-onset severe portal hypertension and twofold to fourfold increase in profibrogenic transcripts Col1a1 [procollagen α1(I)], Tgfb1, and Timp1. Primary liver cancers in BALB/c.Mdr2(-/-) developed earlier, with greater tumor burden compared to FVB.Mdr2(-/-). BALB/c.Mdr2(-/-) mice have unprecedented degree and rapidity of hepatic fibrosis progression and clinically relevant cirrhosis complications, such as early-onset portal hypertension and primary liver cancers. This new model will facilitate development of antifibrotic drugs and studies into mechanisms of biliary fibrosis progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / deficiency*
  • ATP-Binding Cassette Sub-Family B Member 4
  • Animals
  • Cholangitis, Sclerosing* / genetics
  • Cholangitis, Sclerosing* / metabolism
  • Cholangitis, Sclerosing* / pathology
  • Disease Models, Animal
  • Hypertension, Portal* / genetics
  • Hypertension, Portal* / metabolism
  • Hypertension, Portal* / pathology
  • Liver Cirrhosis* / genetics
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism


  • ATP Binding Cassette Transporter, Subfamily B
  • Tgfb1 protein, mouse
  • Timp1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta1