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

Sun Hee Ahn, Zhihao Chen, Jinkyung Lee, Seok Woo Lee, Sang Hyun Min, Nam Doo Kim, Tae Hoon Lee

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Osteoclasts are large multinucleated cells which are induced by the regulation of the receptor activator of nuclear factor kappa-B 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.

Original languageEnglish
Article number3139
JournalMolecules
Volume23
Issue number12
DOIs
StatePublished - 29 Nov 2018

Keywords

  • Bone resorption
  • Cathepsin K
  • Osteoclast
  • Osteoporosis

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