Ivabradine abrogates TNF-α-induced degradation of articular cartilage matrix.

Ivabradine is most commonly used for the treatment of worsening cardiac failure in patients who cannot tolerate the maximum dose of β-blockers or in whom treatment with β-blockers is contraindicated. While ivabradine is regarded as a highly selective "funny current" (I _f ) inhibitor, the molecular mechanism behind the effect of this drug remains poorly understood. In the present study, we applied ivabradine in the context of osteoarthritis by treating primary human chondrocytes with tumor necrosis factor-α (TNF-α) and measuring degradation of the articular cartilage matrix as well as the expression of various enzymes and pro-inflammatory cytokines. Our results indicate that ivabradine significantly abrogated TNF-α-induced up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 at both the gene and protein levels. Notably, ivabradine attenuated TNF-α-induced reduction of type II collagen and aggrecan at both the mRNA and protein levels. Also, we found that ivabradine inhibited the expression and secretion of interleukin-6 (IL-6) and interleukin-1β (IL-1β) as well as the production of reactive oxygen species (ROS). Mechanistically, our results indicate that ivabradine abolished the activation of nuclear factor (NF-κB) by inhibiting nuclear translocation of NF-κB p65. Knockdown of HCN2 enhanced the protective effects of ivabradine against TNF-α- induced degradation of both type II collagen and aggrecan, suggesting that the inhibitory effects of ivabradine in ECM degradation might be mediated by HCN2. Our findings demonstrate that ivabradine may indeed have a potential application in preventing excessive degradation of the articular cartilage matrix, thereby preventing the pathological development and progression of osteoarthritis.
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