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5-Lipoxygenase Mediates RANKL-Induced Osteoclast Formation via the Cysteinyl Leukotriene Receptor 1

Cited 16 time in Web of Science Cited 15 time in Scopus
Authors
Lee, Jung-Min; Park, Hyojung; Noh, A Long Sae Mi; Kang, Ju-Hee; Chen, Ling; Zheng, Ting; Lee, Juhyun; Ji, Sun-Young; Jang, Chang-Young; Shin, Chan Soo; Ha, Hyunil; Lee, Zang Hee; Park, Hea-Young; Lee, Dong-Seok; Yim, Mijung
Issue Date
2012-12
Publisher
American Association of Immunologists
Citation
JOURNAL OF IMMUNOLOGY Vol.189 No.11, pp. 5284-5292
Keywords
복합학
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 I kappa B 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. The Journal of Immunology, 2012, 189: 5284-5292.
ISSN
0022-1767
Language
English
URI
http://hdl.handle.net/10371/82233
DOI
https://doi.org/10.4049/jimmunol.1003738
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College of Dentistry/School of Dentistry (치과대학/치의학대학원)Dept. of Dentistry (치의학과)Journal Papers (저널논문_치의학과)
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