Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts

• Published in: Bone (New York, N.Y.) Vol. 49; no. 6; pp. 1219 - 1231
• Main Authors: Id Boufker, Hichame, Lagneaux, Laurence, Fayyad-Kazan, Hussein, Badran, Bassam, Najar, Mehdi, Wiedig, Murielle, Ghanem, Ghanem, Laurent, Guy, Body, Jean-Jacques, Journé, Fabrice
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01.12.2011
• Subjects: Adolescent; Adult; Alkaline Phosphatase - metabolism; Biological and medical sciences; Biomarkers - metabolism; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Bone Marrow Cells - enzymology; Bone Matrix - drug effects; Bone Matrix - metabolism; Bones, joints and connective tissue. Antiinflammatory agents; Calcification, Physiologic - drug effects; Calcification, Physiologic - genetics; Calcium - metabolism; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Child; Core Binding Factor Alpha 1 Subunit - metabolism; Diphosphonates - pharmacology; DNA - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Silencing - drug effects; Humans; Medical sciences; Orthopedics; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Pharmacology. Drug treatments; Pregnenediones - pharmacology; Protein Binding - drug effects; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stromal Cells - cytology; Stromal Cells - drug effects; Stromal Cells - enzymology; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Young Adult; Farnesoid X receptor; Bone marrow stromal cells; Bile acids; Bisphosphonates; Osteoblasts; Antiosteoporotic; Antiosteoclastic agent; Morphology; Bone marrow; Osteoblast; Stromal cell
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2011.08.013

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.