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
