Antagonism of cysteinyl leukotriene receptor 1 (cysLTR1) by montelukast suppresses cell senescence of chondrocytes

Abstract

Aging is closely associated with osteoarthritis (OA). Although its underlying mechanisms remain unknown, cellular senescence in chondrocytes has become an important therapeutic target for the treatment of OA. Cysteinyl leukotriene receptors (cysLTRs) mediate the pathobiological function of cysteinyl leukotrienes (cysLTs). However, the roles of cysLTRs in the pathogenesis of OA have not been reported before. In the current study, we found that cysLTR1 but not cysLTR2 is expressed in human primary chondrocytes. In addition, stimulation with tumor necrosis factor α (TNF-α) resulted in a significant increase in the expression of cysLTR1. Interestingly, montelukast, a specific cysLTR1 antagonist, attenuated TNF-α-induced up-regulation of the activity of senescence-associated β-galactosidase (SA-β-Gal). In addition, TNF-α led to cell cycle arrest at the G0/G1 phase, which was prevented by treatment with montelukast. Notably, montelukast reduced expression of the senescence markers p53, p21 and PAI-1. In addition, montelukast ameliorated TNF-α-induced K382 acetylation of p53 by promoting the expression of SIRT1. Silencing of SIRT1 using SIRT1 siRNA broke the inhibitory effects of montelukast on K382 acetylation of p53. Importantly, silencing of cysLTR1 reversed the reduction of SIRT1 expression as well as the K382 acetylation of p53. Our findings strongly implicate that cysLTR1 has the capacity to regulate cellular senescence in chondrocytes. It is suggested that montelukast may be a potential therapeutic agent for chondro-protective therapy.

Keywords: Montelukast; Osteoarthritis; P53; Senescence; cysLTR1.