MDR2-/- Mice as Model for Hepatic Osteodystrophy

People suffering from chronic liver diseases often have an increased incidence of bone fractures caused by reduced bone mineralization. Mice deficient in the ABCb4 transporter (MDR2^-/-) suffer from chronic liver disease similar to PBS and PSC. Aim of this study was to analyze changes in bone mineral density and architecture of MDR2^-/- mice over time and to identify possible regulatory mechanisms. MDR2^-/- mice and wildtype controls were sacrificed 5, 7, 9, 11, 13, 15, 20, 30 and 44 weeks after birth (N=4). Progression of liver damage, evaluated by histological staining of the liver (H&E, Masson Goldner Trichrome), as well as LDH and transaminase levels in the serum increased most significantly in MDR2^-/- mice between weeks 5 to 15. Wildtype mice showed no liver damage at all observed time-points. Micro CT analysis showed that bone volume and trabecular number is reduced, while trabecular separation is increased in MDR2^-/- mice from week 20 on. RT-PCR analysis showed that the inflammatory parameters TNF-α and RANKL were increased while osteoprotegerin expression was decreased in livers of MDR2^-/- mice. At the same time osteopontin and osteocalcin expression was significantly reduced in bone of MDR2^-/- mice. Reporter cell analysis revealed that circulating active TGF-β levels decreased with age in wilde-type mice, whereas MDR2^-/- mice had constantly elevated (up to 120 fold at week 30) serum-levels of active TGF-β. Our data show that chronic liver damage in MDR2^-/- mice is associated with reduced bone mineral density. As possible connection, we propose down-regulation of osteoprotegerin expression, which–in combination with increased RANKL–favors osteoclastogenesis. Furthermore, as we previously showed with cultured osteoblasts, continuously high TGF-β levels may inhibit osteoblast function and thus formation of mineralized matrix as presented by down-regulation of osteopontin and osteocalcin.

Hepatic osteodystrophy - MDR2-/- mice - bone mineral density