Bone Abstracts (2013) 1 PP512 | DOI: 10.1530/boneabs.1.PP512

Positive regulation of osteogenesis by bile acid through FXR

Chan Soo Shin1, Sun Wook Cho1, Hyojung Park1, Jae-Yeon Yang1, Sang Wan Kim1, Young Joo Park1, Mijung Yim2, Jung Eun Kim3, Seong Yeon Kim1 & Jee Hyun An4

1Seoul National University College of Medicine, Seoul, Republic of Korea; 2Sookmyung Women’s University, Seoul, Republic of Korea; 3Kyungpook National University School of Medicine, Daegu, Republic of Korea; 4Konkuk University Hospital, Seoul, Republic of Korea.

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, which functions as bile acid sensor controlling the bile acid homeostasis. We have investigated the role of FXR in regulating bone metabolism in vivo. We have identified expression of FXR in calvaria and bone marrow cells, which was gradually increased during osteoblastic differentiation in vitro. Deletion of FXR in vivo has resulted in significant reduction in bone mineral density by 4.3–6.6% from 8 to 20 weeks of age compared with FXR+/+ mice. Micro-computed tomography analysis of distal femur demonstrated significant reduction of trabecular bone volume, trabecular thickness and cortical thickness in FXR−/− mice compared with FXR+/+ mice. Histologic analysis of lumbar spine also showed that FXR deficiency reduced bone formation rate as well as trabecular bone volume and thickness. Moreover, TRACP staining of femurs revealed that both 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 were blunted in primary calvarial cells from FXR−/− mice compared with those from FXR+/+ mice in concert with significant reduction in the Col1a1, ALP, BSP, Runx2 and osterix gene expressions while treatment of C3H10T1/2 cells with bile acids (CDCA or 6-ECDCA) or synthetic FXR agonists (GW4064 or fexaramine) significantly enhanced ALP activities. Interestingly, culture of bone marrow derived macrophages from FXR−/− mice resulted in increased number of osteoclast formation and increased NFATc1 expression compared with those from FXR+/+ mice. Furthermore, treatment of the macrophages with FXR agonists has potently inhibited osteoclast formation. Taken together, these results suggest that FXR positively regulates bone metabolism through both arms of bone remodeling pathways, i.e. bone formation and resorption.

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