title: 5-Lipoxygenase mediates RANKL-induced osteoclast formation via the cysteinyl leukotriene receptor 1.
abstract: 5-Lipoxygenase (5-LO) catalyzes the formation of two major groups of leukotrienes, leukotriene B4 and cysteinyl leukotrienes (CysLTs), and it has been implicated as a promising drug target to treat various inflammatory diseases. However, its role in osteoclastogenesis has not been investigated. In this study, we used mouse bone marrow-derived macrophages (BMMs) to show that 5-LO inhibitor suppresses RANKL-induced osteoclast formation. Inhibition of 5-LO was associated with impaired activation of multiple signaling events downstream of RANK, including ERK and p38 phosphorylation, and IκB degradation, followed by a decrease in NFATc1 expression. Ectopic overexpression of a constitutively active form of NFATc1 partly rescued the antiosteoclastogenic effect of 5-LO inhibitor. The knockdown of 5-LO in BMMs also resulted in a significant reduction in RANKL-induced osteoclast formation, accompanied by decreased expression of NFATc1. Similar effects were shown with CysLT receptor (CysLTR)1/2 antagonist and small RNA for CysLTR1 in BMMs, indicating the involvement of CysLT and CysLTR1 in 5-LO-mediated osteoclastogenesis. Finally, 5-LO inhibitor suppressed LPS-induced osteoclast formation and bone loss in the in vivo mouse experiments, suggesting a potential therapeutic strategy for treating diseases involving bone destruction. Taken together, the results of this study demonstrate that 5-LO is a key mediator of RANKL-induced osteoclast formation and possibly a novel therapeutic target for bone-resorption diseases.
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.forename: Hyojung
authors.initials: H
authors.lastname: Park
authors.forename: A Long Sae Mi
authors.initials: AL
authors.lastname: Noh
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Ting
authors.initials: T
authors.lastname: Zheng
authors.forename: Juhyun
authors.initials: J
authors.lastname: Lee
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Ji
authors.forename: Chang-Young
authors.initials: CY
authors.lastname: Jang
authors.forename: Chan Soo
authors.initials: CS
authors.lastname: Shin
authors.forename: Hyunil
authors.initials: H
authors.lastname: Ha
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.forename: Hea-Young
authors.initials: HY
authors.lastname: Park
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Lee
authors.forename: Mijung
authors.initials: M
authors.lastname: Yim
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D001094:Arachidonate 5-Lipoxygenase; D048049:Extracellular Signal-Regulated MAP Kinases; D051550:I-kappa B Kinase; D007211:Indoles; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D034741:RNA, Small Interfering; D018077:Receptors, Leukotriene; D048051:p38 Mitogen-Activated Protein Kinases; C494005:Nfatc1 protein, mouse; C505689:Tnfsf11 protein, mouse; C060893:MK-886; D002722:Chlorobenzenes; C083169:leukotriene D4 receptor