title: Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts.
abstract: Bone tissue contains bile acids which accumulate from serum and which can be released in large amounts in the bone microenvironment during bone resorption. However, the direct effects of bile acids on bone cells remain largely unexplored. Bile acids have been identified as physiological ligands of the farnesoid X receptor (FXR, NR1H4). In the present study, we have examined the effects of FXR activation/inhibition on the osteoblastic differentiation of human bone marrow stromal cells (BMSC). We first demonstrated the expression of FXR in BMSC and SaOS2 osteoblast-like cells, and observed that FXR activation by chenodeoxycholic acid (CDCA) or by farnesol (FOH) increases the activity of alkaline phosphatase and the calcification of the extracellular matrix. In addition, we observed that FXR agonists are able to stimulate the expression of osteoblast marker genes [bone sialoprotein (BSP), osteocalcin (OC), osteopontin (OPN) and alkaline phosphatase (ALP)] (FXR involvement validated by shRNA-induced gene silencing), as well as the DNA binding activity of the bone transcription factor RUNX2 (EMSA and ChIP assay). Importantly, we observed that nitrogen-containing bisphosphonates (BPs) inhibit the basal osteoblastic differentiation of BMSC, possibly through suppression of endogenous FOH production, independently of their effects on protein prenylation. Likewise, we found that the FXR antagonist guggulsterone (GGS) inhibits ALP activity, calcium deposition, DNA binding of RUNX2, and bone marker expression, indicating that GGS interferes with osteoblastic differentiation. Furthermore, GGS induced the appearance of lipid vesicles in BMSC and stimulated the expression of adipose tissue markers (peroxisome proliferator activated receptor-gamma (PPARγ), adipoQ, leptin and CCAAT/enhancer-binding protein-alpha (C/EBPα)). In conclusion, our data support a new role for FXR in the modulation of osteoblast/adipocyte balance: its activation stimulates RUNX2-mediated osteoblastic differentiation of BMSC, whereas its inhibition leads to an adipocyte-like phenotype.
authors: Laboratoire d'Hématologie Expérimentale, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors: Hichame
authors: H
authors: Id Boufker
authors: Laurence
authors: L
authors: Lagneaux
authors: Hussein
authors: H
authors: Fayyad-Kazan
authors: Bassam
authors: B
authors: Badran
authors: Mehdi
authors: M
authors: Najar
authors: Murielle
authors: M
authors: Wiedig
authors: Ghanem
authors: G
authors: Ghanem
authors: Guy
authors: G
authors: Laurent
authors: Jean-Jacques
authors: JJ
authors: Body
authors: Fabrice
authors: F
authors: Journé
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011282:Pregnenediones / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D055815:Young Adult; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000469:Alkaline Phosphatase; D015415:Biomarkers; D002118:Calcium; D050659:Core Binding Factor Alpha 1 Subunit; D004247:DNA; D004164:Diphosphonates; D011282:Pregnenediones; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C493709:RUNX2 protein, human; C023617:pregna-4,17-diene-3,16-dione