Agelasine D Suppresses RANKL-Induced Osteoclastogenesis via Down-Regulation of c-Fos, NFATc1 and NF-κB
1
Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea
2
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea
3
College of Pharmacy, Chungbuk National University, 52 Naesudongro, Cheongju 361-763, Korea
4
Department of Microbiology & Molecular Biology, Chungnam National University, 99 Daehakro, Daejeon 305-764, Korea
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Mar. Drugs 2014, 12(11), 5643-5656; https://doi.org/10.3390/md12115643
Received: 27 August 2014 / Revised: 31 October 2014 / Accepted: 12 November 2014 / Published: 24 November 2014
In the present study, we investigated the effect of agelasine D (AD) on osteoclastogenesis. Treatment of bone marrow macrophages (BMMs) with receptor activator of nuclear factor κB ligand (RANKL) resulted in a differentiation of BMMs into osteoclasts as evidenced by generation of tartrate-resistant acid phosphatase (TRAP)-positive, multinucleated cells and formation of pits in calcium phosphate-coated plates. However, RANKL-induced osteoclastogenesis was significantly suppressed by AD treatment. We also confirmed the increased mRNA and protein expression of osteoclastic markers, such as TRAP, cathepsin K and matrix metalloproteinase-9, during RANKL-induced osteoclast differentiation and this was down-regulated by AD treatment. Moreover, AD treatment significantly suppressed RANKL-induced mRNA expression of DC-STAMP and OC-STAMP and cell fusion of TRAP-positive mononuclear osteoclast precursors. In addition, AD suppressed RANKL-induced expression of transcription factors, c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are important transcription factors involved in differentiation of BMMs into osteoclasts. Furthermore, RANKL-induced phosphorylation of extracellular signal-related kinase (ERK) and activation of NF-κB were also inhibited by AD treatment. Collectively, these results suggest that AD inhibits RANKL-induced osteoclastogenesis by down-regulation of multiple signaling pathways involving c-Fos, NFATc1, NF-κB and ERK. Our results also suggest that AD might be a potential therapeutic agent for prevention and treatment of osteoporosis.
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Keywords:
agelasine D; osteoclastogenesis; c-Fos; NF-ATc1; NF-κB
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MDPI and ACS Style
Kang, M.R.; Jo, S.A.; Yoon, Y.D.; Park, K.H.; Oh, S.J.; Yun, J.; Lee, C.W.; Nam, K.-H.; Kim, Y.; Han, S.-B.; Yu, J.; Rho, J.; Kang, J.S. Agelasine D Suppresses RANKL-Induced Osteoclastogenesis via Down-Regulation of c-Fos, NFATc1 and NF-κB. Mar. Drugs 2014, 12, 5643-5656.
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