Marta Dubreuil

Effects of bilirubin and sera from jaundiced patients on osteoblasts: Contribution to the development of osteoporosis in liver diseases†

Low bone formation is considered to be the main feature in osteoporosis associated with cholestatic and end‐stage liver diseases, although the consequences of retained substances in chronic cholestasis on bone cells have scarcely been studied. Therefore, we analyzed the effects of bilirubin and serum from jaundiced patients on viability, differentiation, mineralization, and gene expression in the cells involved in bone formation. The experiments were performed in human primary osteoblasts and SAOS‐2 human osteosarcoma cells. Unconjugated bilirubin or serum from jaundiced patients resulted in a dose‐dependent decrease in osteoblast viability. Concentrations of bilirubin or jaundiced serum without effects on cell survival significantly diminished osteoblast differentiation. Mineralization was significantly reduced by exposure to 50 μM bilirubin at all time points (from −32% to −55%) and jaundiced sera resulted in a significant decrease on cell mineralization as well. Furthermore, bilirubin down‐regulated RUNX2 (runt‐related transcription factor 2) gene expression, a basic osteogenic factor involved in osteoblast differentiation, and serum from jaundiced patients significantly up‐regulated the RANKL/OPG (receptor activator of nuclear factor‐κB ligand/osteoprotegerin) gene expression ratio, a system closely involved in osteoblast‐induced osteoclastogenesis. Conclusion: Besides decreased cell viability, unconjugated bilirubin and serum from jaundiced patients led to defective consequences on osteoblasts. Moreover, jaundiced serum up‐regulates the system involved in osteoblast‐induced osteoclastogenesis. These results support the deleterious consequences of increased bilirubin in advanced chronic cholestasis and in end‐stage liver diseases, resulting in disturbed bone formation related to osteoblast dysfunction. (HEPATOLOGY 2011)

Ursodeoxycholic acid increases differentiation and mineralization and neutralizes the damaging effects of bilirubin on osteoblastic cells.

Osteoporosis resulting from decreased bone formation is a common complication in patients with chronic cholestasis. Lithocholic acid (LCA) and bilirubin may play a role in osteoporosis given that both substances have detrimental effects on survival of human osteoblasts, the cells involved in bone formation.

Ursodeoxycholic acid decreases bilirubin-induced osteoblast apoptosis.

Low bone turnover osteoporosis is common in cholestatic diseases. Ursodeoxycholic acid (UDCA) counteracts the damaging effects of bilirubin or lithocholic acid (LCA) on osteoblast viability, proliferation and mineralisation. UDCA is anti‐apoptotic in various cell lines, but this effect in bone cells is unknown. Therefore, the consequences of bilirubin and LCA on apoptosis, and whether UDCA has anti‐apoptotic effects have been assessed on osteoblasts.

1306 URSODEOXYCHOLIC ACID NEUTRALIZES THE NOXIOUS EFFECTS OF LITHOCHOLIC ACID AND BILIRUBIN ON OSTEOBLASTS

did not differ between the two groups. ALT response was inversely correlated with HA, BDL and F score, while ALP response was inversely correlated with BDL score. In addition, positive anti-gp210 antibodies was significantly associated with poor response of both ALT and ALP. Conclusions: Positive anti-gp210 antibodies is a significant risk factor for poor biochemical response to UDCA treatment in Japanese patients with PBC.