5-Lipoxygenase Mediates RANKL-Induced Osteoclast Formation via the Cysteinyl Leukotriene Receptor 1
- 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
- 1-Dec-2012
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Citation
- JOURNAL OF IMMUNOLOGY, v.189, no.11, pp 5284 - 5292
- Pages
- 9
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Volume
- 189
- Number
- 11
- Start Page
- 5284
- End Page
- 5292
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/11793
- DOI
- 10.4049/jimmunol.1003738
- ISSN
- 0022-1767
1550-6606
- 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.
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