Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-<i>N</i>-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression
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 hav...
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MDPI AG
2018-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/23/12/3139 |
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| author | Sun-Hee Ahn Zhihao Chen Jinkyung Lee Seok-Woo Lee Sang Hyun Min Nam Doo Kim Tae-Hoon Lee |
| author_facet | Sun-Hee Ahn Zhihao Chen Jinkyung Lee Seok-Woo Lee Sang Hyun Min Nam Doo Kim Tae-Hoon Lee |
| author_sort | Sun-Hee Ahn |
| collection | DOAJ |
| description | 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)-<i>N</i>-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. |
| first_indexed | 2024-12-10T05:47:48Z |
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| last_indexed | 2024-12-10T05:47:48Z |
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| series | Molecules |
| spelling | doaj.art-9d64bd037764448bb5052d02f772ccd02022-12-22T02:00:07ZengMDPI AGMolecules1420-30492018-11-012312313910.3390/molecules23123139molecules23123139Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-<i>N</i>-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K ExpressionSun-Hee Ahn0Zhihao Chen1Jinkyung Lee2Seok-Woo Lee3Sang Hyun Min4Nam Doo Kim5Tae-Hoon Lee6Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, KoreaDepartment of Molecular Medicine (BK21plus), Chonnam National University Graduate School, Gwangju 61186, KoreaDepartment of Molecular Medicine (BK21plus), Chonnam National University Graduate School, Gwangju 61186, KoreaDepartment of Dental Education and Periodontology, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Dong-gu, Daegu 41061, KoreaNDBio Therapeutics Inc., S24 Floor, Songdogwahak-ro 32, Yeonsu-gu, Incheon 21984, KoreaDepartment of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju 61186, KoreaOsteoclasts 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)-<i>N</i>-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.https://www.mdpi.com/1420-3049/23/12/3139osteoclastcathepsin Kosteoporosisbone resorption |
| spellingShingle | Sun-Hee Ahn Zhihao Chen Jinkyung Lee Seok-Woo Lee Sang Hyun Min Nam Doo Kim Tae-Hoon Lee Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-<i>N</i>-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression Molecules osteoclast cathepsin K osteoporosis bone resorption |
| title | Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-<i>N</i>-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression |
| title_full | Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-<i>N</i>-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression |
| title_fullStr | Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-<i>N</i>-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression |
| title_full_unstemmed | Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-<i>N</i>-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression |
| title_short | Inhibitory Effects of 2N1HIA (2-(3-(2-Fluoro-4-Methoxyphenyl)-6-Oxo-1(6H)-Pyridazinyl)-<i>N</i>-1H-Indol-5-Ylacetamide) on Osteoclast Differentiation via Suppressing Cathepsin K Expression |
| title_sort | inhibitory effects of 2n1hia 2 3 2 fluoro 4 methoxyphenyl 6 oxo 1 6h pyridazinyl i n i 1h indol 5 ylacetamide on osteoclast differentiation via suppressing cathepsin k expression |
| topic | osteoclast cathepsin K osteoporosis bone resorption |
| url | https://www.mdpi.com/1420-3049/23/12/3139 |
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