International Journal of Medical Sciences

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12 December 2017

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Int J Med Sci 2017; 14(9):840-852. doi:10.7150/ijms.19268

Research Paper

The Simultaneous Inhibitory Effect of Niclosamide on RANKL-Induced Osteoclast Formation and Osteoblast Differentiation

Fei-Lan Liu1,2#, Chun-Liang Chen3#, Chia-Chung Lee3, Cheng-Chi Wu1,3, Teng-Hsu Hsu1, Chang-Youh Tsai1, Hsu-Shan Huang3, Deh-Ming Chang1,2,3✉

1. Rheumatology/Immunology/Allergy, Taipei Veterans General Hospital, Taiwan, Republic of China
2. Graduate Institute of Medical Sciences, National Defense Medical Center, Taiwan, Republic of China
3. Graduate Institutes of Life Sciences, National Defense Medical Center, Taiwan, Republic of China
# Both authors contributed equally to this work.

Abstract

The bone destruction disease including osteoporosis and rheumatoid arthritis are caused by the imbalance between osteoblastogenesis and osteoclastogenesis. Inhibition of the NF-κB pathway was responsible for decreased osteoclastogenesis. Recently many studies indicated that niclosamide, the FDA approved an antihelminth drug, inhibits prostate and breast cancer cells growth by targeting NF-κB signaling pathways. This study evaluated the effects of niclosamide on osteoclast and osteoblast differentiation and function in vitro.

In RANKL-induced murine osteoclast precursor cell RAW264.7 and M-CSF/RANKL-stimulated primary murine bone marrow-derived macrophages (BMM), niclosamide dose-dependently inhibited the formation of TRAP-positive multinucleated osteoclasts and resorption pits formation between 0.5uM and 1uM. In addition, niclosamide suppressed the expression of nuclear factor of activated T cells c1 (NFATc1) and osteoclast differentiated-related genes in M-CSF/ RANKL-stimulated BMM by interference with TRAF-6, Erk1/2, JNK and NF-κB activation pathways. However, the cytotoxic effects of niclosamide obviously appeared at the effective concentrations for inhibiting osteoclastogenesis (0.5-1uM) with increase of apoptosis through caspase-3 activation in osteoblast precursor cell line, MC3T3-E1. Niclosamide also inhibited ALP activity, bone mineralization and osteoblast differentiation-related genes expression in MC3T3-E1. Therefore, our findings suggest the new standpoint that niclosamide's effects on bones must be considered before applying it in any therapeutic treatment.

Keywords: Niclosamide, Osteoclast Formation, Osteoblast Differentiation

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How to cite this article:
Liu FL, Chen CL, Lee CC, Wu CC, Hsu TH, Tsai CY, Huang HS, Chang DM. The Simultaneous Inhibitory Effect of Niclosamide on RANKL-Induced Osteoclast Formation and Osteoblast Differentiation. Int J Med Sci 2017; 14(9):840-852. doi:10.7150/ijms.19268. Available from http://www.medsci.org/v14p0840.htm