Format

Send to

Choose Destination
Mol Med Rep. 2018 Aug;18(2):2387-2398. doi: 10.3892/mmr.2018.9179. Epub 2018 Jun 15.

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

Author information

1
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University, Seoul 140‑742, Republic of Korea.
2
Department of Physics, Hunter College of The City University of New York, New York, NY 10065, USA.
3
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.

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.

PMID:
29916540
DOI:
10.3892/mmr.2018.9179
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Spandidos Publications
Loading ...
Support Center