Authors
Sun Wook Cho MD, Jee Hyun An MD, Hyojung Park PhD, Jae-Yeon Yang MS, Hyung Jin Choi MD, Sang Wan Kim MD, Young Joo Park MD, Seong Yeon Kim MD, Mijung Yim PhD, Wook-Young Baek PhD, Jung-Eun Kim MD, Chan Soo Shin MD
Abstract
Farnesoid X receptor (FXR) is a nuclear receptor, which 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∼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, 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 Col1a1, ALP, and Runx2 gene expressions. Cultures of bone marrow derived macrophages from FXR−/− mice exhibited an increased number of osteoclast formations and protein expression of NFATc1. In female FXR−/− mice, although 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 (CDCA or 6-ECDCA) or FXR agonists (GW4064 or Fexaramine) significantly enhanced osteoblastic differentiation through the upregulation of Runx2 and enhanced ERK and β-catenin signaling. FXR agonists also suppressed osteoclast differentiation from bone marrow macrophages. Finally, administration of a farnesol diet (1%) marginally prevented 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, i.e. bone formation and resorption.