Farnesoid X receptor (FXR) is a nuclear receptor that functions as a bile acid 
sensor controlling bile acid homeostasis. We investigated the role of FXR in 
regulating bone metabolism. We identified the expression of FXR in calvaria and 
bone marrow cells, which gradually increased during osteoblastic differentiation 
in vitro. In male mice, deletion of FXR (FXR(-/-) ) in vivo resulted in a 
significant reduction in bone mineral density by 4.3% to 6.6% in mice 8 to 20 
weeks of age compared with FXR(+/+) mice. Histological analysis of the lumbar 
spine showed that FXR deficiency reduced the bone formation rate as well as the 
trabecular bone volume and thickness. Moreover, tartrate-resistant acid 
phosphatase (TRACP) staining of the femurs revealed that both the osteoclast 
number and osteoclast surface were significantly increased in FXR(-/-) mice 
compared with FXR(+/+) mice. At the cellular level, induction of alkaline 
phosphatase (ALP) activities was blunted in primary calvarial cells in FXR(-/-) 
mice compared with FXR(+/+) mice in concert with a significant reduction in type 
I collagen a1(Col1a1), ALP, and runt-related transcription factor 2 (Runx2) gene 
expressions. Cultures of bone marrow-derived macrophages from FXR(-/-) mice 
exhibited an increased number of osteoclast formations and protein expression of 
nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). In female FXR(-/-) 
mice, although bone mineral density (BMD) was not significantly different from 
that in FXR(+/+) mice, bone loss was accelerated after an ovariectomy compared 
with FXR(+/+) mice. In vitro, activation of FXR by bile acids (chenodeoxycholic 
acid [CDCA] or 6-ECDCA) or FXR agonists (GW4064 or Fexaramine) significantly 
enhanced osteoblastic differentiation through the upregulation of Runx2 and 
enhanced extracellular signal-regulated kinase (ERK) and β-catenin signaling. 
FXR agonists also suppressed osteoclast differentiation from bone marrow 
macrophages. Finally, administration of a farnesol (FOH 1%) diet marginally 
prevented ovariectomy (OVX)-induced bone loss and enhanced bone mass gain in 
growing C57BL/6J mice. Taken together, these results suggest that FXR positively 
regulates bone metabolism through both arms of the bone remodeling pathways; ie, 
bone formation and resorption.