PT  - JOURNAL ARTICLE
AU  - Silvia Ruiz-Gaspà
AU  - Nuria Guañabens
AU  - Susana Jurado González
AU  - Marta Dubreuil
AU  - Andres Combalia
AU  - Pilar Peris
AU  - Ana Monegal
AU  - Albert Parés
TI  - Bile acids and bilirubin effects on osteoblastic gene profile. Implications in the pathogenesis of osteoporosis in liver diseases
AID  - 10.1101/705871
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 705871
4099  - http://biorxiv.org/content/early/2019/07/17/705871.short
4100  - http://biorxiv.org/content/early/2019/07/17/705871.full
AB  - 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.