title: 5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression.
abstract: 5-Lipoxygenase synthesizes leukotrienes from arachidonic acid. We developed three novel 5-LO inhibitors having a benzoxazole scaffold as a potential anti-osteoclastogenics. They significantly suppressed RANKL-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, one compound, K7, inhibited the bone resorptive activity of osteoclasts. The anti-osteoclastogenic effect of K7 was mainly attributable to reduction in the expression of NFATc1, an essential transcription factor for osteoclast differentiation. K7 inhibited osteoclast formation via ERK and p38 MAPK, as well as NF-κB signaling pathways. K7 reduced lipopolysaccharide (LPS)-induced osteoclast formation in vivo, corroborating the in vitro data. Thus, K7 exerted an inhibitory effect on osteoclast formation in vitro and in vivo, properties that make it a potential candidate for the treatment of bone diseases associated with excessive bone resorption.
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ting
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
authors.forename: Mi-ran
authors.initials: MR
authors.lastname: Moon
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
authors.forename: Jung-Seon
authors.initials: JS
authors.lastname: Sim
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Kyung-Eun
authors.initials: KE
authors.lastname: Doh
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Sunhye
authors.initials: S
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Minghua
authors.initials: M
authors.lastname: Cui
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Hyeun Wook
authors.initials: HW
authors.lastname: Chang
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: hypark@ewha.ac.kr.
authors.forename: Hea-Young
authors.initials: HY
authors.lastname: Park Choo
authors.affiliation: College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea. Electronic address: myim@soomyung.ac.kr.
authors.forename: Mijung
authors.initials: M
authors.lastname: Yim
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D017434:Protein Structure, Tertiary; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012886:Skull / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D001094:Arachidonate 5-Lipoxygenase; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 5-Lipoxygenase; Benzoxazole scaffold; Lipopolysaccharide (LPS)-induced osteoclast formation; NFATc1; RANKL-induced osteoclast formation