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Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-N-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression

1
Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, Korea
2
Department of Molecular Medicine (BK21plus), Chonnam National University Graduate School, Gwangju 61186, Korea
3
Department of Dental Education and Periodontology, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, Korea
4
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Dong-gu, Daegu 41061, Korea
5
NDBio Therapeutics Inc., S24 Floor, Songdogwahak-ro 32, Yeonsu-gu, Incheon 21984, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2018, 23(12), 3139; https://doi.org/10.3390/molecules23123139
Received: 8 November 2018 / Revised: 22 November 2018 / Accepted: 26 November 2018 / Published: 29 November 2018
(This article belongs to the Section Medicinal Chemistry)
Osteoclasts are large multinucleated cells which are induced by the regulation of the receptor activator of nuclear factor kappa-Β ligand (RANKL), which is important in bone resorption. Excessive osteoclast differentiation can cause pathologic bone loss and destruction. Numerous studies have targeted molecules inhibiting RANKL signaling or bone resorption activity. In this study, 11 compounds from commercial libraries were examined for their effect on RANKL-induced osteoclast differentiation. Of these compounds, only 2-(3-(2-fluoro-4-methoxyphenyl)-6-oxo-1(6H)-pyridazinyl)-N-1H-indol-5-ylacetamide (2N1HIA) caused a significant decrease in multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cell formation in a dose-dependent manner, without inducing cytotoxicity. The 2N1HIA compound neither affected the expression of osteoclast-specific gene markers such as TRAF6, NFATc1, RANK, OC-STAMP, and DC-STAMP, nor the RANKL signaling pathways, including p38, ERK, JNK, and NF-κB. However, 2N1HIA exhibited a significant impact on the expression levels of CD47 and cathepsin K, the early fusion marker and critical protease for bone resorption, respectively. The activity of matrix metalloprotease-9 (MMP-9) decreased due to 2N1HIA treatment. Accordingly, bone resorption activity and actin ring formation decreased in the presence of 2N1HIA. Taken together, 2N1HIA acts as an inhibitor of osteoclast differentiation by attenuating bone resorption activity and may serve as a potential candidate in preventing and/or treating osteoporosis, or other bone diseases associated with excessive bone resorption. View Full-Text
Keywords: osteoclast; cathepsin K; osteoporosis; bone resorption osteoclast; cathepsin K; osteoporosis; bone resorption
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Ahn, S.-H.; Chen, Z.; Lee, J.; Lee, S.-W.; Min, S.H.; Kim, N.D.; Lee, T.-H. Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-N-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression. Molecules 2018, 23, 3139.

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