Lithocholic acid downregulates vitamin D effects in human osteoblasts.
BACKGROUND
Osteoporosis is a common complication in chronic cholestasis. It has been proposed that retained substances such as bile acids may produce a damaging effect on bone cells. This study analyses the effects of lithocholic acid (LCA) on cell survival and vitamin D metabolism in human osteoblasts (hOB).


METHODS
Human osteoblasts cultures were performed with or without foetal bovine serum (FBS) or human albumin (HA) at different LCA concentrations and times with or without vitamin D.


RESULTS
Lithocholic acid at concentrations higher than 10(-5 )M decreased cell survival. This effect was partially prevented by the presence of FBS or HA. Vitamin D stimulated CYP24A, BGLAP and TNFSF11 expression in hOB and these effects were modified by nontoxic LCA concentrations. LCA significantly decreased vitamin D stimulation of CYP24A, BGLAP and TNFSF11 gene expression at 72%, 79% and 56% (respectively). LCA alone has an agonistic effect, as has vitamin D, thus partially increasing CYP24A and BGLAP expression, but with no changes on TNFRSF11B expression. Equivalent effects of the LCA were observed by performing gene reporter assays using MG-63 cells transfected with constructs containing CYP24A1 promoter regions.


CONCLUSIONS
Lithocholic acid decreases the stimulatory effect of vitamin D on CYP24A, BGLAP and TNFSF11 expression in hOB. This effect is produced through vitamin D response elements (VDREs), located in the promoter regions of these genes, suggesting that LCA acts as a mild analogous of vitamin D, interacting with the vitamin D receptor. These results may explain the potential deleterious effects of retained bile acids on hOB.
Ruiz-Gaspà
S
S
Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. silvia.ruiz@ciberehd.org
Guañabens
N
N
Enjuanes
A
A
Peris
P
P
Martinez-Ferrer
A
A
de Osaba
M J Martinez
MJ
Gonzalez
B
B
Alvarez
L
L
Monegal
A
A
Combalia
A
A
Parés
A
A
D002470:Cell Survival; D002478:Cells, Cultured; D002779:Cholestasis / Q000150:complications* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D008095:Lithocholic Acid / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D015675:Osteocalcin / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism*; D053244:Osteoprotegerin / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D053245:RANK Ligand / Q000187:drug effects / Q000378:metabolism; D012313:RNA / Q000235:genetics; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014807:Vitamin D / Q000378:metabolism* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase
D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D015675:Osteocalcin; D014807:Vitamin D; D008095:Lithocholic Acid; D012313:RNA; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase