Z Gastroenterol 2009; 47 - P321
DOI: 10.1055/s-0029-1241569

BALB-Abcb4 mice lacking the hepatobiliary phospholipid transporter represent a potential model of hepatic osteodystrophy

K Hochrath 1, B Rathkolb 2, 3, K Butuzova 2, 3, W Hans 3, H Fuchs 3, V Gailus-Durner 3, E Wolf 2, M Hrabé de Angelis 3, F Lammert 1
  • 1Universität des Saarlandes, Universitätsklinikum des Saarlandes, Innere Medizin 2, Homburg, Germany
  • 2Institute of Molecular Animal Breeding and Biotechnology, LMU Munich, München, Germany
  • 3Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany

Aims: Metabolic bone disease occurring in patients with chronic cholestasis, known as hepatic osteodystrophy, is a potential complication of long-standing liver diseases. Abcb4 (Mdr2) knockout mice develop chronic cholangitis due to the lack of phosphatidylcholine from bile. This mouse model resembles progressive familial intrahepatic cholestasis type 3 in humans, which is caused by mutations of the orthologous phosphatidylcholine transporter and may lead to cirrhosis in early childhood. In an attempt to characterize the systemic consequences of ABCB4 deficiency, we now phenotyped these mice in standardised, comprehensive workflows (Nat Methods 2005;2:403).

Methods: We generated congenic mice by introgressing the Abcb4 knockout from the FVB/NJ strain into the fibrosis-susceptible BALB/cJ background for 10 generations. At 16–20 weeks of age, 10 BALB-Abcb4 -/- mice of each gender and 20 wild-type control mice (BALB/cJ) were phenotyped, using clinical chemical assays, X-ray analysis (Faxitron MX-20) and a pDEXA Sabre X-ray bone densitometer.

Results: As expected, BALB-Abcb4 -/- mice showed significant increases in liver enzymes (ALT, AP) as compared to wild-type controls. Of note, bone mineral content and bone content were significantly (p<0.05) reduced in male (347±35 vs. 492±24mg) and female knockout mice (1.31±0.13 vs. 1.65±0.06%), respectively. No genotype-specific observations were made in X-ray analysis. Plasma calcium levels were decreased (p<0.01), whereas inorganic phosphorus was significantly increased (p<0.001), consistent with lower 25OH-vitamin D3 levels in male BALB-Abcb4 -/- mice.

Conclusions: BALB-Abcb4 knockout mice on a vitamin D-supplemented diet display subtle alterations of calcium metabolism and bone densitometry. These might be due to multiple pathophysiological mechanisms including vitamin deficiency, hyperbilirubinemia and proinflammatory cytokines, all of which may also contribute to hepatic osteodystrophy in humans with chronic cholestasis.

This work was supported by grants from the European Community (EUMODIC LSHG-2006–037188) to the German Mouse Clinic and from the Bundesministerium für Bildung und Forschung (NGFNplus) to DB (01GS0852), EW (01GS0851), and to MHA (01GS0850).