PDF(Pubmed)
Abstract：
Knee osteoarthritis (KOA) is a major cause of disability in elderly individuals. Dicoumarol is a coumarin‑like compound derived from sweet clover [Melilotus officinalis (L.) Pall]. It has been suggested that dicoumarol exhibits various types of pharmacological activities, including anticoagulant, antitumor and antibacterial effects. Due to its various biological activities, dicoumarol has a potential protective effect against OA. Therefore, the present study aimed to assess the effects of dicoumarol on knee osteoarthritis. In the present study, dicoumarol was found to protect rat synoviocytes from lipopolysaccharide (LPS)‑induced cell apoptosis. Western blot analysis showed that dicoumarol significantly reduced the protein expression levels of fibrosis‑related markers and inflammatory cytokines (Tgfb, Timp, Col1a, Il1b and Il18). The inhibitory rates of these proteins were all >50% (P<0.01) compared with those in the LPS and ATP‑induced group. Consistently, the mRNA expression levels of these markers and cytokines were decreased to normal levels by dicoumarol after the treatment of rat synovial fibroblasts with LPS and ATP. Mechanistic studies demonstrated that dicoumarol did not affect NF‑κB signaling, but it did directly interact with NOD‑like receptor protein 3 (NLRP3) to promote its protein degradation, which could be reversed by MG132, but not NH4Cl. The protein half‑life of NLRP3 was accelerated from 26.1 to 4.3 h by dicoumarol. Subsequently, dicoumarol could alleviate KOA in vivo; knee joint diameter was decreased from 11.03 to 9.93 mm. Furthermore, the inflammation and fibrosis of the knee joints were inhibited in rats. In conclusion, the present findings demonstrated that dicoumarol could impede the progression of KOA by inhibiting NLRP3 activation, providing a potential treatment strategy for KOA.
摘要：
膝关节骨性关节炎(KOA)是老年人致残的主要原因。Dicoumarol是一种类似香豆素的化合物，来自甜三叶草[Melilotusofficinalis（L.）鲍尔]。有人认为，双香豆酚表现出各种类型的药理活性，包括抗凝剂,抗肿瘤和抗菌作用。由于其各种生物活性，双香豆酚对OA具有潜在的保护作用。因此,本研究旨在评估双香豆酚对膝骨关节炎的影响。在本研究中,发现双香豆酚可保护大鼠滑膜细胞免受脂多糖（LPS）诱导的细胞凋亡。Westernblot分析表明，双香豆酚显着降低了纤维化相关标志物和炎性细胞因子的蛋白表达水平（Tgfb，Timp,Col1a,Il1b和Il18）。与LPS和ATP诱导组相比，这些蛋白的抑制率均>50％（P<0.01）。始终如一，用LPS和ATP处理大鼠滑膜成纤维细胞后，双香豆酚将这些标志物和细胞因子的mRNA表达水平降低至正常水平。机制研究表明，双香豆素不影响NF‑κB信号传导，但它确实直接与NOD样受体蛋白3（NLRP3）相互作用以促进其蛋白质降解，MG132可以逆转，但NH4Cl不能逆转。双香豆酚使NLRP3的蛋白质半衰期从26.1h加速到4.3h。随后，双香豆酚可缓解体内KOA；膝关节直径从11.03mm减小到9.93mm。此外，抑制了大鼠膝关节的炎症和纤维化。总之,本研究结果表明，双香豆素可以通过抑制NLRP3激活来阻止KOA的进展，为KOA提供潜在的治疗策略。
