It has been certainly demonstrated that lithocholic acid decreases the stimulatory effect of vitamin D on osteocalcin and RANKL mRNA expression in primary human osteoblasts,6 results which may explain the potential deleterious effects of retained bile acids on bone formation in patients with chronic cholestasis. There are controversies on the potential detrimental effects of increased unconjugated hyperbilirubinemia (usually below 68 μM) associated with Gilbert’s syndrome in the development of low bone mass and osteoporosis. Thus, some studies have pointed out an association between osteoporosis and Gilbert’s syndrome,12 whereas other

studies categorically selleck inhibitor oppose such association.11 A recent study of PFT�� datasheet hyperbilirubinemic Gunn rats also failed to show a difference between bone mineral density and osteocalcin levels in hyperbilirubinenic rats and wild-type rats, suggesting that elevated serum bilirubin alone is not a major contributory factor to hepatic osteodystrophy that results in low bone

mass in this animal model.11 The results of the current study cannot refute this latter study, but are in favor of such a relationship between low bone mass and hyperbilirubinemia, because the effect of unconjugated bilirubin on cell viability, differentiation, and mineralization were observed with bilirubin concentrations present in patients with Gilbert’s syndrome (50 μM), but not with the experiments performed with normal bilirubin concentrations in nonjaundiced patients and in healthy subjects. The recent study showing BCKDHA a significant inverse correlation between unconjugated bilirubin

levels and total body bone mineral density in a series of 17 subjects with Gilbert’s syndrome may support our findings.12 In summary, our results indicate that unconjugated bilirubin and sera from jaundiced patients lead to clearly defective consequences in primary human osteoblasts and in an osteoblast cell line, besides decreased cell viability. Moreover, sera from jaundiced patients induced significant up-regulation of the RANKL/OPG ratio involved in osteoclastogenesis, and bilirubin down-regulated RUNX2 gene expression, a transcription factor related to osteoblastogenesis. Taken together, these data sustain the deleterious consequences of increased bilirubin in advanced chronic cholestatic diseases and in end-stage liver diseases on the development of bone loss, resulting from disturbed bone formation related to osteoblast dysfunction. This study was supported in part by CIBERehd and PI080105, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain.