Montelukast inhibits RANKL‑induced osteoclast formation and bone loss via CysLTR1 and P2Y12

Kang,Ju‑Hee; Lim,Hyungsik; Lee,Dong‑Seok; Yim,Mijung

doi:10.3892/mmr.2018.9179

Montelukast inhibits RANKL‑induced osteoclast formation and bone loss via CysLTR1 and P2Y12

Authors:
- Ju‑Hee Kang
- Hyungsik Lim
- Dong‑Seok Lee
- Mijung Yim
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Affiliations: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University, Seoul 140‑742, Republic of Korea, Department of Physics, Hunter College of The City University of New York, New York, NY 10065, USA, Department of Natural Sciences, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
Published online on: June 15, 2018 https://doi.org/10.3892/mmr.2018.9179
Pages: 2387-2398

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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‑κB 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 Cγ2 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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1	Zaidi M: Skeletal remodeling in health and disease. Nat Med. 13:791–801. 2007. View Article : Google Scholar : PubMed/NCBI
2	Rodan GA and Martin TJ: Therapeutic approaches to bone diseases. Science. 289:1508–1514. 2000. View Article : Google Scholar : PubMed/NCBI
3	Boyle WJ, Simonet WS and Lacey DL: Osteoclast differentiation and activation. Nature. 423:337–342. 2003. View Article : Google Scholar : PubMed/NCBI
4	Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT and Martin TJ: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 20:345–357. 1999. View Article : Google Scholar : PubMed/NCBI
5	Lee ZH and Kim HH: Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem Biophys Res Commun. 305:211–214. 2003. View Article : Google Scholar : PubMed/NCBI
6	Moon JB, Kim JH, Kim K, Youn BU, Ko A, Lee SY and Kim N: Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. J Immunol. 188:163–169. 2012. View Article : Google Scholar : PubMed/NCBI
7	Faccio R and Cremasco V: PLCgamma2: Where bone and immune cells find their common ground. Ann N Y Acad Sci. 1192:124–130. 2010. View Article : Google Scholar : PubMed/NCBI
8	Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, et al: Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 3:889–901. 2002. View Article : Google Scholar : PubMed/NCBI
9	Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, Asahara H, Ohya K, Yamaguchi A, Takai T, et al: Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med. 12:1410–1416. 2006. View Article : Google Scholar : PubMed/NCBI
10	Negishi-Koga T and Takayanagi H: Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev. 131:241–256. 2009. View Article : Google Scholar
11	Singh RK, Gupta S, Dastidar S and Ray A: Cysteinyl leukotrienes and their receptors: Molecular and functional characteristics. Pharmacology. 85:336–349. 2010. View Article : Google Scholar : PubMed/NCBI
12	Nayak A: A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opin Pharmacother. 5:679–686. 2004. View Article : Google Scholar : PubMed/NCBI
13	Theron AJ, Steel HC, Tintinger GR, Gravett CM, Anderson R and Feldman C: Cysteinyl leukotriene receptor-1 antagonists as modulators of innate immune cell function. J Immunol Res. 2014:6089302014. View Article : Google Scholar : PubMed/NCBI
14	Hikiji H, Takato T, Shimizu T and Ishii S: The roles of prostanoids, leukotrienes and platelet-activating factor in bone metabolism and disease. Prog Lipid Res. 47:107–126. 2008. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Method. 25:402–208. 2001. View Article : Google Scholar
16	Ishijima M, Rittling SR, Yamashita T, Tsuji K, Kurosawa H, Nifuji A, Denhardt DT and Noda M: Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin. J Exp Med. 193:399–404. 2001. View Article : Google Scholar : PubMed/NCBI
17	Virchow JC and Bachert C: Efficacy and safety of montelukast in adults with asthma and allergic rhinitis. Respir Med. 100:1952–1959. 2006. View Article : Google Scholar : PubMed/NCBI
18	Wagner EF and Karsenty G: Genetic control of skeletal development. Curr Opin Genet Dev. 11:527–532. 2001. View Article : Google Scholar : PubMed/NCBI
19	Wada T, Nakashima T, Hiroshi N and Penninger JM: RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 12:17–25. 2006. View Article : Google Scholar : PubMed/NCBI
20	Ha H, Lee JH, Kim HN, Kim HM, Kwak HB, Lee S, Kim HH and Lee ZH: alpha-Lipoic acid inhibits inflammatory bone resorption by suppressing prostaglandin E2 synthesis. J Immunol. 176:111–117. 2006. View Article : Google Scholar : PubMed/NCBI
21	Riccioni G, Bucciarelli T, Mancini B, Di Ilio C and D'Orazio N: Antileukotriene drugs: Clinical application, effectiveness and safety. Curr Med Chem. 14:1966–1977. 2007. View Article : Google Scholar : PubMed/NCBI
22	Paggiaro P and Bacci E: Montelukast in asthma: A review of its efficacy and place in therapy. Ther Adv Chronic Dis. 2:47–58. 2011. View Article : Google Scholar : PubMed/NCBI
23	Kim N, Takami M, Rho J, Josien R and Choi Y: A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med. 195:201–209. 2002. View Article : Google Scholar : PubMed/NCBI
24	Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, et al: Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature. 428:758–763. 2004. View Article : Google Scholar : PubMed/NCBI
25	Ferron M, Boudiffa M, Arsenault M, Rached M, Pata M, Giroux S, Elfassihi L, kisseleva M, Majerus PW, Rousseau F and Vacher J: Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans. Cell Metab. 14:466–477. 2011. View Article : Google Scholar : PubMed/NCBI
26	Kim H, Kim T, Jeong BC, Cho IT, Han D, Takegahara N, Negishi-Koga T, Takayanagi H, Lee JH, Sul JY, et al: Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation. Cell Metab. 17:249–260. 2013. View Article : Google Scholar : PubMed/NCBI
27	Di Capite J, Shirley A, Nelson C, Bates G and Parekh AB: Intercellular Ca2+ wave propagation involving positive feedback between CRAC channels and cysteinyl leukotrienes. FASEB J. 3:894–905. 2009. View Article : Google Scholar
28	Tintinger GR, Feldman C, Theron AJ and Anderson R: Montelukast: More than a cysteinyl leukotriene receptor antagonist? Sci World J. 10:2403–2413. 2010. View Article : Google Scholar
29	Fredriksson R, Lagerstrom MC, Lundin LG and Schioth HB: The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups and fingerprints. Mol Pharmacol. 63:1256–1272. 2003. View Article : Google Scholar : PubMed/NCBI
30	Nonaka Y, Hiramoto T and Fujita N: Identification of endogenous surrogate ligands for human P2Y12 receptors by in silico and in vitro methods. Biochem Biophys Res Commun. 337:281–288. 2005. View Article : Google Scholar : PubMed/NCBI
31	Finsterer J and Frank M: Repurposed drugs in metabolic disorders. Curr Top Med Chem. 13:2386–2394. 2013. View Article : Google Scholar : PubMed/NCBI