title: Agelasine D suppresses RANKL-induced osteoclastogenesis via down-regulation of c-Fos, NFATc1 and NF-κB.
abstract: 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.
authors.affiliation: Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. kangmr@kribb.re.kr.
authors.forename: Moo Rim
authors.initials: MR
authors.lastname: Kang
authors.affiliation: Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. jsunada123@naver.com.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Jo
authors.affiliation: Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. yunyd76@hanmail.net.
authors.forename: Yeo Dae
authors.initials: YD
authors.lastname: Yoon
authors.affiliation: Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. brightnessd@nate.com.
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Park
authors.affiliation: Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. diatree@kribb.re.kr.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Oh
authors.affiliation: Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. jyun@kribb.re.kr.
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.affiliation: Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. changwoo@kribb.re.kr.
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. namk@kribb.re.kr.
authors.forename: Ki-Hoan
authors.initials: KH
authors.lastname: Nam
authors.affiliation: College of Pharmacy, Chungbuk National University, 52 Naesudongro, Cheongju 361-763, Korea. youngsoo@chungbuk.ac.kr.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungbuk National University, 52 Naesudongro, Cheongju 361-763, Korea. shan@chungbuk.ac.kr.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: Department of Microbiology & Molecular Biology, Chungnam National University, 99 Daehakro, Daejeon 305-764, Korea. julmooni@hanmail.net.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Microbiology & Molecular Biology, Chungnam National University, 99 Daehakro, Daejeon 305-764, Korea. jrrho@cnu.ac.kr.
authors.forename: Jaerang
authors.initials: J
authors.lastname: Rho
authors.affiliation: Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanjiro, Cheongju 363-883, Korea. kanjon@kribb.re.kr.
authors.forename: Jong Soon
authors.initials: JS
authors.lastname: Kang
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D015536:Down-Regulation; D005260:Female; D007527:Isoenzymes / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics; D050778:NFATC Transcription Factors / Q000235:genetics; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011687:Purines / Q000494:pharmacology*; D053245:RANK Ligand / Q000008:administration & dosage* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D011687:Purines; D053245:RANK Ligand; D012333:RNA, Messenger; C509934:agelasine D; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase