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

Abstract

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 lM bilirubin at all time points (from 232% to 255%) 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-jB 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;54:2104-2113

In Vitro Hepatic Trans-Differentiation of Human Mesenchymal Stem Cells Using Sera from Congestive/Ischemic Liver during Cardiac Failure

“…Since the cardiac jaundiced sera possess higher concentration of HGF, we assume that 5% sera induced hepatic differentiation of hMSCs with no significant effect on cell viability. Although, 10% sera also contain higher concentration of HGF, its anti-apoptotic and anti-necrotic effects would have been suppressed by the higher concentration of bilirubin and bile acids [52], [53]. Nevertheless, high serum level of HGF released from damaged heart/liver in such cases could effectively potentiate hepatic induction, comparable to that of known recombinant hepatogenic factors [20]–[22].…”

A Case of Autoimmune Hepatitis and Bisphosphonate-Related Osteonecrosis of the Jaw

“…AIH may significantly contribute to BRONJ development in case of poor hepatic synthetic function, as high unconjugated and conjugated bilirubin levels are associated with decreased osteoblast viability and increased osteoclastogenesis [6]. The latter effect may be neutralized by potent BP agents, thus critically interfering with bone remodelling in the jaw.…”

“…These include prolonged corticosteroid exposure and, because of impaired synthetic hepatic function, high unconjugated bilirubin and impaired conversion of vitamin D to 25-hydroxy vitamin D [5, 6]. For this reason, bisphosphonate (BP) treatment is widely used in these patients [5].…”

Risk Factors Associated with Left-Sided Cardiac Valve Calcification: A Case Control Study

“…We speculate that a potential reason for the discrepancy between results is the differences in the study populations. Ruiz-Gaspa et al [23] reported that bilirubin inhibits bone formation and that a high bilirubin level leads to osteoporosis in end-stage liver disease. As valve calcification is an ectopic mineralization and has similar mechanisms to bone formation [7,9], we speculate that bilirubin could not prevent the formation of valve calcification; however, a positive relationship between a higher bilirubin level and valve calcification might indicate a compensatory anticalcification effect of bilirubin.…”