Research Papers:

The farnesoid X receptor negatively regulates osteoclastogenesis in bone remodeling and pathological bone loss

Ting Zheng, Ju-Hee Kang, Jung-Sun Sim, Jung-Woo Kim, Jeong-Tae Koh, Chan Soo Shin, Hyungsik Lim and Mijung Yim _

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Oncotarget. 2017; 8:76558-76573. https://doi.org/10.18632/oncotarget.20576

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Ting Zheng1,*, Ju-Hee Kang1,*, Jung-Sun Sim1, Jung-Woo Kim2, Jeong-Tae Koh2, Chan Soo Shin3, Hyungsik Lim4 and Mijung Yim1

1College of Pharmacy, Sookmyung Women’s University, Yongsan-ku, Seoul, Republic of Korea

2Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea

3Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea

4Departments of Physics, Hunter College of the City University of New York, New York City, New York, USA

*These authors contributed equally to this work

Correspondence to:

Mijung Yim, email: [email protected]

Keywords: FXR, osteoclast, RANKL, NFATc1, bone loss

Received: July 18, 2017     Accepted: August 09, 2017     Published: August 28, 2017


Farnesoid X receptor (FXR, NR1H4) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. Since the role of FXR in osteoclast differentiation remains ill-defined, we investigated the biological function of FXR on osteoclastogenesis, using FXR-deficient mice. We demonstrated that FXR deficiency increases osteoclast formation in vitro and in vivo. First, FXR deficiency was found to accelerate osteoclast formation via down-regulation of c-Jun N-terminal kinase (JNK) 1/2 expression. Increased expression of peroxisome proliferator-activated receptor (PPAR)γ and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1)β seems to mediate the pro-osteoclastogenic effect of FXR deficiency via the JNK pathway. In addition, we found that FXR deficiency downregulated the expression of interferon-β (IFN-β), a strong inhibitor of osteoclastogenesis, via receptor activator of nuclear factor-kappaB ligand (RANKL). We further suggested that interference of IFN-β expression by FXR deficiency impaired the downstream JAK3-STAT1 signaling pathways, which in turn increased osteoclast formation. Finally, FXR deficiency accelerated unloading- or ovariectomy-induced bone loss in vivo. Thus, our findings demonstrate that FXR is a negative modulator in osteoclast differentiation and identify FXR as a potential therapeutic target for postmenopausal osteoporosis and unloading-induced bone loss.

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