Excessive bone resorption induced by abnormal osteoclast differentiation has been associated with bone microstructure damage and bone-associated disorders, including osteoporosis. Here, we investigated the physiological roles of the type 1 cysteinyl leukotriene receptor (cysLTR-1) and the pharmacological functions of the specific cysLTR-1 antagonist montelukast on M-CSF- and RANKL-induced osteoclast differentiation. We showed that cysLTR-1 but not cysLTR-2 is expressed in osteoclast precursor cells: mouse bone marrow-derived macrophages (BMMs). We also found that treatment with M-CSF and RANKL significantly increased expression of cysLTR-1. Overexpression of cysLTR-1 promoted osteoclast differentiation of BMMs by increasing NFATc1 and TRAP. In contrast, treatment with montelukast prevented M-CSF- and RANKL-induced osteoclast differentiation of BMMs. Mechanically, our findings demonstrate that montelukast treatment attenuated activation of the ERK1/2, p38, JNK and NF-κB signalling pathways. Additionally, we reported that montelukast treatment ameliorated the generation of ROS and calcium signalling. Importantly, the co-immunoprecipitation assay displayed that montelukast treatment prevented the interaction of RANK and TRAF6. Finally, in vivo experiments indicated that montelukast rescued the reduction of bone volume as well as trabecular number in an ovariectomy mouse model.
Keywords: Osteoclast differentiation; RANKL; montelukast; osteoporosis; type 1 cysteinyl leukotriene receptor.