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

• Published in: The Journal of immunology (1950) 2012-12, Vol.189 (11), p.5284-5292
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Arachidonate 5-Lipoxygenase - genetics; Arachidonate 5-Lipoxygenase - metabolism; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - pathology; Bone Resorption - genetics; Bone Resorption - metabolism; Bone Resorption - prevention & control; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Indoles - pharmacology; Lipopolysaccharides - pharmacology; Lipoxygenase Inhibitors - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Mice; Mice, Inbred ICR; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoclasts - pathology; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; RANK Ligand - antagonists & inhibitors; RANK Ligand - genetics; RANK Ligand - metabolism; Receptors, Leukotriene - genetics; Receptors, Leukotriene - metabolism; RNA, Small Interfering - genetics; Signal Transduction - drug effects
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1003738

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.