J Bone Metab.  2017 Nov;24(4):207-215. 10.11005/jbm.2017.24.4.207.

Fexaramine Inhibits Receptor Activator of Nuclear Factor-κB Ligand-induced Osteoclast Formation via Nuclear Factor of Activated T Cells Signaling Pathways

• Zheng T
• Kim NY
• Yim M

• KMID: 2397553
• DOI: http://doi.org/10.11005/jbm.2017.24.4.207

Abstract

BACKGROUND
Osteoclasts are bone resorbing cells and are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Fexaramine has been developed as an agonist for the farnesoid X receptor (FXR). This study investigated the effects of fexaramine on receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclast formation and signaling pathways.
METHODS
Osteoclasts were formed by culturing mouse bone marrow-derived macrophages (BMMs) with macrophage colony-stimulating factor (M-CSF) and RANKL. Bone resorption assays were performed using dentine slices. The mRNA expression level was analyzed by real-time polymerase chain reaction. Western blotting assays were conducted to detect the expression or activation level of proteins. Lipopolysaccharide-induced osteoclast formation was performed using a mouse calvarial model.
RESULTS
Fexaramine inhibited RANKL-induced osteoclast formation, without cytotoxicity. Furthermore, fexaramine diminished the RANKL-stimulated bone resorption. Mechanistically, fexaramine blocked the RANKL-triggered p38, extracellular signal-regulated kinase, and glycogen synthase kinase 3β phosphorylation, resulting in suppressed expression of c-Fos and NF of activated T cells (NFATc1). Consistent with the in vitro anti-osteoclastogenic effect, fexaramine suppressed lipopolysaccharide-induced osteoclast formation in the calvarial model.
CONCLUSIONS
The present data suggest that fexaramine has an inhibitory effect on osteoclast differentiation and function, via downregulation of NFATc1 signaling pathways. Thus, fexaramine could be useful for the treatment of bone diseases associated with excessive bone resorption.

Keyword

Genes fos; NF-kappa B; Osteoclasts; RANK Ligand

MeSH Terms

Animals
Arthritis, Rheumatoid
Blotting, Western
Bone Diseases
Bone Resorption
Dentin
Down-Regulation
Glycogen Synthase Kinases
In Vitro Techniques
Macrophage Colony-Stimulating Factor
Macrophages
Mice
NF-kappa B
Osteoclasts*
Osteoporosis
Periodontitis
Phosphorylation
Phosphotransferases
RANK Ligand
Real-Time Polymerase Chain Reaction
RNA, Messenger
T-Lymphocytes*
Glycogen Synthase Kinases
Macrophage Colony-Stimulating Factor
NF-kappa B
Phosphotransferases
RANK Ligand
RNA, Messenger