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5-Lipoxygenase mediates RANKL-induced osteoclast formation via the cysteinyl leukotriene receptor 1

Title
5-Lipoxygenase mediates RANKL-induced osteoclast formation via the cysteinyl leukotriene receptor 1
Authors
Lee J.-M.Park H.Noh A.L.S.M.Kang J.-H.Chen L.Zheng T.Lee J.Ji S.-Y.Jang C.-Y.Shin C.S.Ha H.Lee Z.H.Park H.-Y.Lee D.-S.Yim M.
Ewha Authors
박혜영
SCOPUS Author ID
박혜영scopus
Issue Date
2012
Journal Title
Journal of Immunology
ISSN
0022-1767JCR Link
Citation
vol. 189, no. 11, pp. 5284 - 5292
Indexed
SCI; SCIE; SCOPUS WOS scopus
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 IkB 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 boneresorption diseases. Copyright © 2012 by The American Association of Immunologists, Inc.
DOI
10.4049/jimmunol.1003738
Appears in Collections:
약학대학 > 약학과 > Journal papers
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