Graduate Institute of Life Science, National Defense Medical Center, Taipei 11490, Taiwan.
Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Miaoli 35053, Taiwan.
Int J Mol Sci. 2018 Mar 12;19(3):825. doi: 10.3390/ijms19030825.
Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen-induced arthritis (CIA) animal model in this study. Chondrocytes were prepared from cartilage specimens taken from pigs or OA patients. Western blotting, quantitative PCR, and immunohistochemistry were adopted to measure the expression of collagen II (Col II) and matrix metalloproteinases (MMP). DXM significantly restored tumor necrosis factor-alpha (TNF-α)-mediated reduction of collagen II and decreased TNF-α-induced MMP-13 production. To inhibit the synthesis of MMP-13, DXM blocked TNF-α downstream signaling, including I kappa B kinase (IKK)α/β-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) activation. Besides this, DXM protected the CIA mice from severe inflammation and cartilage destruction. DXM seemed to protect cartilage from inflammation-mediated matrix degradation, which is an irreversible status in the disease progression of osteoarthritis. The results suggested that testing DXM as an osteoarthritis therapeutic should be a focus in further research.
骨关节炎（OA）是最常见的关节疾病，主要影响老年人。理想的抗 OA 药物应具有适度的抗炎作用，并且长期使用仅有有限的或无毒性。由于镇咳药右美沙芬（DXM）在动脉粥样硬化和神经系统疾病（老年人的两种常见疾病）中具有保护作用，因此我们在这项研究中研究了 DXM 是否可以在促炎细胞因子刺激的软骨细胞和胶原诱导性关节炎（CIA）动物模型中发挥保护作用。软骨细胞取自猪或 OA 患者的软骨标本。采用 Western blot、定量 PCR 和免疫组织化学方法测量胶原 II（Col II）和基质金属蛋白酶（MMP）的表达。DXM 显著恢复了肿瘤坏死因子-α（TNF-α）介导的胶原 II 减少，并降低了 TNF-α诱导的 MMP-13 产生。为了抑制 MMP-13 的合成，DXM 阻断了 TNF-α下游信号通路，包括 IκB 激酶（IKK）α/β-IκBα-核因子-κB（NF-κB）和 c-Jun N 末端激酶（JNK）-激活蛋白-1（AP-1）激活。除此之外，DXM 还保护 CIA 小鼠免受严重的炎症和软骨破坏。DXM 似乎可以保护软骨免受炎症介导的基质降解，这是骨关节炎疾病进展中不可逆转的状态。结果表明，将 DXM 作为治疗骨关节炎的药物进行测试应该是进一步研究的重点。
