Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
J Bone Miner Res. 2013 Oct;28(10):2109-21. doi: 10.1002/jbmr.1961.
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.
法尼醇 X 受体 (FXR) 是一种核受体，作为胆汁酸传感器发挥作用，控制胆汁酸稳态。我们研究了 FXR 在调节骨代谢中的作用。我们在颅骨和骨髓细胞中鉴定出了 FXR 的表达，其在体外成骨细胞分化过程中逐渐增加。在雄性小鼠中，体内 FXR 的缺失（FXR(-/-)）导致 8 至 20 周龄小鼠的骨矿物质密度显著降低 4.3%至 6.6%，与 FXR(+/+)小鼠相比。腰椎组织学分析显示，FXR 缺乏减少了骨形成率以及小梁骨体积和厚度。此外，股骨的抗酒石酸酸性磷酸酶 (TRACP) 染色显示，FXR(-/-)小鼠的破骨细胞数量和破骨细胞表面均显著增加，与 FXR(+/+)小鼠相比。在细胞水平上，FXR(-/-)小鼠原代颅骨细胞中碱性磷酸酶 (ALP) 活性的诱导减弱，同时 I 型胶原 a1(Col1a1)、ALP 和 runt 相关转录因子 2 (Runx2) 基因表达显著降低。FXR(-/-)小鼠骨髓来源巨噬细胞的培养物显示破骨细胞形成数量增加，核因子活化 T 细胞，细胞质 1 (NFATc1) 蛋白表达增加。在雌性 FXR(-/-) 小鼠中，尽管骨矿物质密度 (BMD) 与 FXR(+/+) 小鼠无显著差异，但与 FXR(+/+) 小鼠相比，卵巢切除后骨丢失加速。体外，胆汁酸（鹅脱氧胆酸 [CDCA] 或 6-ECDCA）或 FXR 激动剂（GW4064 或 Fexaramine）激活 FXR 通过上调 Runx2 显著增强成骨细胞分化，并增强细胞外信号调节激酶 (ERK) 和 β-连环蛋白信号。FXR 激动剂还抑制骨髓巨噬细胞向破骨细胞的分化。最后，法尼醇（FOH 1%）饮食的给药可轻微预防卵巢切除（OVX）引起的骨丢失，并增强生长中的 C57BL/6J 小鼠的骨量增加。综上所述，这些结果表明 FXR 通过骨重塑途径的两个分支（骨形成和骨吸收）积极调节骨代谢。
