title: Inhibition of RANKL- and LPS-induced osteoclast differentiations by novel NF-κB inhibitor DTCM-glutarimide.
abstract: We have isolated 9-methylstreptimidone from microorganism as a new NF-κB inhibitor. Later, we designed 3-[(dodecylthiocarbonyl) methyl]-glutarimide (DTCM-glutarimide) as an analog of this compound, which shows anti-inflammatory activity in vivo. In the present research, we found that DTCM-glutarimide inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation of mouse bone marrow-derived macrophages and RANKL- or lipopolysaccharide (LPS)-induced osteoclast differentiation of RAW 264.7 cells without any toxicity. It also inhibited the RANKL-induced NFATc1 expression. Upstream signaling involving phosphorylation of Akt and GSK-3β was induced by RANKL, of which the signaling was inhibited by DTCM-glutarimide. Then DTCM-glutarimide was confirmed to inhibit RANKL-induced NF-κB activity, possibly by inhibiting the Akt-mediated activation of IKK. Thus, DTCM-glutarimide inhibited osteoclastogenesis by blocking both the Akt-GSK3β-NFATc1 and NF-κB-NFATc1 pathways. DTCM-glutarimide may be a candidate as a chemotherapeutic agent for severe bone resorption diseases.
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Koide
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama 223-0061, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kaneda
authors.affiliation: Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
authors.affiliation: Department of Molecular Target Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan. Electronic address: umezawa@aichi-med-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D010881:Piperidones / Q000138:chemical synthesis / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C573776:3-((dodecylthiocarbonyl)methyl)glutarimide; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D010881:Piperidones; D053245:RANK Ligand; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3
keywords: Akt; DTCM-glutarimide; LPS; NF-κB; Osteoclastogenesis; RANKL