Osteoarthritis (OA) is a major cause of joint pain and disability, resulting in large socioeconomic costs worldwide. Isofraxidin (ISO), a bioactive coumarin compound isolated from the functional foods Siberian ginseng and Apium graveolens, exerts anti-inflammatory effects in a variety of diseases. However, no studies have reported the protective effects of ISO against OA development. Accordingly, this study aimed to assess the therapeutic effect of ISO in human OA chondrocytes, and in a mouse model of OA induced by destabilisation of the medial meniscus (DMM). In vitro, lipopolysaccharide (LPS)-induced overproduction of nitric oxide (NO), prostaglandin E2 (PGE2), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) was decreased by ISO pre-treatment. Furthermore, ISO attenuated the increased expression of inflammatory enzymes, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), in response to LPS stimulation. Meanwhile, LPS-induced extracellular matrix (ECM) degradation was also reversed by ISO treatment. Mechanistically, ISO competitively inhibited Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex formation, and thus TLR4/nuclear factor kappa B (NF-κB) signalling cascades. In vivo, ISO treatment not only prevented the calcification and erosion of cartilage, as well as the thickening of subchondral bone, but also reduced the serum levels of inflammatory cytokines in the mouse OA model. Taken together, these data suggest that ISO has potential in the treatment of OA.

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异氟西丁靶向TLR4 / MD-2轴以预防骨关节炎的发展†

骨关节炎（OA）是关节疼痛和残疾的主要原因，在世界范围内造成了巨大的社会经济成本。异氟西丁（ISO）是一种从功能性食品西伯利亚人参和芹菜中分离出来的具有生物活性的香豆素化合物，可在多种疾病中发挥抗炎作用。然而，尚无研究报道ISO对OA发展的保护作用。因此，本研究旨在评估ISO在人OA软骨细胞以及在内侧半月板（DMM）失稳诱导的OA小鼠模型中的治疗效果。体外，ISO预处理可减少脂多糖（LPS）诱导的一氧化氮（NO），前列腺素E2（PGE2），肿瘤坏死因子-α（TNF-α）和白介素6（IL-6）的过量生产。此外，响应于LPS刺激，ISO减弱了包括诱导型一氧化氮合酶（iNOS）和环氧合酶2（COX-2）在内的炎症酶表达的增加。同时，通过ISO处理也可以逆转LPS诱导的细胞外基质（ECM）降解。机械上，ISO竞争性抑制Toll样受体4（TLR4）/髓样分化蛋白2（MD-2）复合物的形成，并因此抑制TLR4 /核因子κB（NF-κB）信号级联。体内，ISO治疗不仅可以防止软骨的钙化和侵蚀，以及软骨下骨的增厚，还可以降低小鼠OA模型中炎症细胞因子的血清水平。综上所述，这些数据表明ISO在OA的治疗方面具有潜力。