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Montelukast inhibits RANKL-induced osteoclast formation and bone loss via CysLTR1 and P2Y12open access

Authors
Kang, Ju-HeeLim, HyungsikLee, Dong-SeokYim, Mijung
Issue Date
Aug-2018
Publisher
SPANDIDOS PUBL LTD
Keywords
montelukast; cysteinyl leukotriene receptor 1 antagonist; P2Y12; osteoclast; nuclear factor-B ligand; nuclear factor of activated T cells 1; bone loss
Citation
MOLECULAR MEDICINE REPORTS, v.18, no.2, pp 2387 - 2398
Pages
12
Journal Title
MOLECULAR MEDICINE REPORTS
Volume
18
Number
2
Start Page
2387
End Page
2398
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/4391
DOI
10.3892/mmr.2018.9179
ISSN
1791-2997
1791-3004
Abstract
Osteoclasts (OCs) are resorptive cells responsible for bone erosion in diseases, including osteoporosis, periodontitis and rheumatoid arthritis. Montelukast is a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist clinically used for the treatment of asthma. In the present study, the role of CysLTR1 on OC formation and bone loss was investigated using montelukast. Montelukast inhibited receptor activator of nuclear factor-B ligand (RANKL)-induced OC formation in cultures of mouse bone marrow macrophages. Additionally, montelukast suppressed actin ring formation and bone resorption activity of differentiated OCs. The inhibitory effect of montelukast was associated with impaired activation of extracellular signal-regulated kinase, AKT serine/threonine kinase, and/or phospholipase C2 signaling pathways downstream of RANK, followed by decreased expression of nuclear factor of activated T cells c1. Notably, OC formation was efficiently restored by addition of adenosine diphosphate, a P2Y12 agonist, as well as by addition of CysLT. Furthermore, similar to montelukast, P2Y12 blockade by a pharmacological inhibitor or siRNAs suppressed OC differentiation. These data indicate the involvement of the P2Y12 receptor in the inhibitory effect of montelukast on osteoclastogenesis. In vivo, montelukast significantly inhibited inflammation-induced osteoclastogenesis in the calvarial model. Montelukast also served a protective role in a murine ovariectomy (OVX)- and unloading-induced bone loss model. Altogether, these results confirmed that the CysLTR1 antagonist exerted an inhibitory effect on OC formation in vitro and in vivo. It may be useful for the treatment of bone diseases associated with excessive bone resorption.
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