Bile acids and bilirubin effects on osteoblastic gene profile. Implications in the pathogenesis of osteoporosis in liver diseases

Abstract

Osteoporosis in advanced cholestatic and end-stage liver disease is related to low bone formation. Previous studies have demonstrated the deleterious consequences of lithocholic acid (LCA) and bilirubin on osteoblastic cells. These effects are partially or completely neutralized by ursodeoxycholic acid (UDCA). We have assessed the differential gene expression of osteoblastic cells under different culture conditions. The experiments were performed in human osteosarcoma cells (Saos-2) cultured with LCA 10 μM), bilirubin (50 μM) or UDCA (10 and 100 μM) at 2 and 24 hours. Expression of 87 genes related to bone metabolism and other signalling pathways were assessed by TaqMan micro fluidic cards. Several genes were up-regulated by LCA, most of them pro-apoptotic (BAX, BCL10, BCL2L13, BCL2L14), but also MGP (matrix Gla protein), BGLAP (osteocalcin), SPP1 (osteopontin) and CYP24A1, and down-regulated bone morphogenic protein genes (BMP3 and BMP4) and DKK1 (Dickkopf-related protein 1). Parallel effects were observed with bilirubin, which up-regulated apoptotic genes and CSF2 (colony-stimulating factor 2) and down-regulated antiapoptotic genes (BCL2 and BCL2L1), BMP3, BMP4 and RUNX2. UDCA 100 μM had specific consequences since differential expression was observed, up-regulating BMP2, BMP4, BMP7, CALCR (calcitonin receptor), SPOCK3 (osteonectin), BGLAP (osteocalcin) and SPP1 (osteopontin), and down-regulating pro-apoptotic genes. Furthermore, most of the differential expression changes induced by both LCA and bilirubin were partially or completely neutralized by UDCA. Conclusion: Our observations reveal novel target genes, whose regulation by retained substances of cholestasis may provide additional insights into the pathogenesis of osteoporosis in cholestatic and end-stage liver diseases.

Bile Acid Signaling and Cardioprotection

“…Duan et al, [110] shows that nigral cells suspension pre-treated with TUDCA prior to transplant in the brain of rat Parkinson's disease model exhibited low apoptosis activity and increased the survival of grafted cells. Apart from that, UDCA effect on CMs and osteosarcoma fibroblast has also been reported [111]. UDCA shows to inhibit the effect of bilirubin and LCA induces apoptosis in osteoblastic cells by preventing translocation of pro-apoptotic protein BAX to mitochondria and decrease in caspase-3 activity.…”

The Impact of Bariatric Surgery on Bone Health: State of the Art and New Recognized Links

“…Interestingly, different types of BA can have differing effects on bone. Ursodeoxycholic acid inhibits apoptosis and increases survival and differentiation of human osteoblasts, thus neutralizing the detrimental effects of lithocholic acid in these processes 142 . The effects of BA on bone among patients submitted to BS are still not known, and this could be another interesting line of future research.…”