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Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts.
Bone. 2011 Dec; 49(6):1219-31.BONE

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+Show Affiliations

Laboratoire d'Hématologie Expérimentale, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21893226

Citation

Id Boufker, Hichame, et al. "Role of Farnesoid X Receptor (FXR) in the Process of Differentiation of Bone Marrow Stromal Cells Into Osteoblasts." Bone, vol. 49, no. 6, 2011, pp. 1219-31.
Id Boufker H, Lagneaux L, Fayyad-Kazan H, et al. Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts. Bone. 2011;49(6):1219-31.
Id Boufker, H., Lagneaux, L., Fayyad-Kazan, H., Badran, B., Najar, M., Wiedig, M., Ghanem, G., Laurent, G., Body, J. J., & Journé, F. (2011). Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts. Bone, 49(6), 1219-31. https://doi.org/10.1016/j.bone.2011.08.013
Id Boufker H, et al. Role of Farnesoid X Receptor (FXR) in the Process of Differentiation of Bone Marrow Stromal Cells Into Osteoblasts. Bone. 2011;49(6):1219-31. PubMed PMID: 21893226.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts. AU - Id Boufker,Hichame, AU - Lagneaux,Laurence, AU - Fayyad-Kazan,Hussein, AU - Badran,Bassam, AU - Najar,Mehdi, AU - Wiedig,Murielle, AU - Ghanem,Ghanem, AU - Laurent,Guy, AU - Body,Jean-Jacques, AU - Journé,Fabrice, Y1 - 2011/08/26/ PY - 2011/04/26/received PY - 2011/08/11/revised PY - 2011/08/15/accepted PY - 2011/9/7/entrez PY - 2011/9/7/pubmed PY - 2012/3/21/medline SP - 1219 EP - 31 JF - Bone JO - Bone VL - 49 IS - 6 N2 - 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. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/21893226/Role_of_farnesoid_X_receptor__FXR__in_the_process_of_differentiation_of_bone_marrow_stromal_cells_into_osteoblasts_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(11)01156-2 DB - PRIME DP - Unbound Medicine ER -