Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China; Department of Oral and Cranio-maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Free Radic Biol Med. 2019 Dec;145:146-160. doi: 10.1016/j.freeradbiomed.2019.09.024. Epub 2019 Sep 21.
Osteoarthritis (OA) is a progressive joint disorder that is primarily characterized by the degeneration and destruction of the articular cartilage. Cartilage matrix degradation, production of proinflammatory mediators, chondrocyte apoptosis and activation of macrophages in the synovial are involved in OA pathogenesis. Current non-surgical therapies for OA mainly aim at relieving pain but can barely alleviate the progression of OA. Quercetin, a naturally occurring flavonoid has shown potent anti-inflammatory effects, however, its effects and underlying mechanisms on OA have seldom been systematically illuminated. In this study, we explored the protective effects of quercetin on repairing OA-induced cartilage injuries and its possible mechanisms. In vitro, quercetin remarkably suppressed the expression of matrix degrading proteases and inflammatory mediators, meantime promoted the production of cartilage anabolic factors in interleukin-1β-induced (IL-1β) rat chondrocytes. In addition, quercetin exhibited anti-apoptotic effects by decreasing intracellular reactive oxygen species (ROS), restoring mitochondrial membrane potential (MMP) and inhibiting the Caspase-3 pathway in apoptotic rat chondrocytes. Moreover, quercetin induced M2 polarization of macrophages and upregulated the expression of transforming growth factor β (TGF-β) and insulin-like growth factor (IGF), which in turn created a pro-chondrogenic microenvironment for chondrocytes and promoted the synthesis of glycosaminoglycan (GAG) in chondrocytes. In vivo, intra-articular injection of quercetin alleviated the degradation of the cartilage and the apoptosis of chondrocytes in a rat OA model. Moreover, the expression of TGF-β1 and TGF-β2 in the synovial fluid and the ratio of M2 macrophages in the synovial membrane were elevated. In summary, our study proves that quercetin exerts chondroprotective effects by inhibiting inflammation and apoptosis of chondrocytes, modulating synovial macrophages polarization to M2 macrophages and creating a pro-chondrogenic environment for chondrocytes to enhance cartilage repair under OA environment. It is suggested that quercetin may serve as a potential drug for OA treatment.
骨关节炎（OA）是一种进行性关节疾病，主要特征为关节软骨的退化和破坏。软骨基质降解、促炎介质产生、软骨细胞凋亡和滑膜巨噬细胞激活参与 OA 发病机制。目前 OA 的非手术治疗主要旨在缓解疼痛，但几乎不能缓解 OA 的进展。槲皮素是一种天然存在的类黄酮，具有很强的抗炎作用，但其对 OA 的作用及其潜在机制很少被系统阐明。在这项研究中，我们探讨了槲皮素修复 OA 诱导的软骨损伤的保护作用及其可能的机制。在体外，槲皮素显著抑制基质降解蛋白酶和炎症介质的表达，同时促进白细胞介素-1β（IL-1β）诱导的大鼠软骨细胞中软骨合成因子的产生。此外，槲皮素通过减少细胞内活性氧（ROS）、恢复线粒体膜电位（MMP）和抑制凋亡大鼠软骨细胞中的 Caspase-3 途径发挥抗凋亡作用。此外，槲皮素诱导巨噬细胞向 M2 极化，并上调转化生长因子-β（TGF-β）和胰岛素样生长因子（IGF）的表达，这反过来为软骨细胞创造了一个有利于软骨生成的微环境，并促进软骨细胞中糖胺聚糖（GAG）的合成。在体内，关节内注射槲皮素可减轻大鼠 OA 模型中软骨的降解和软骨细胞的凋亡。此外，滑液中 TGF-β1 和 TGF-β2 的表达以及滑膜中 M2 巨噬细胞的比例升高。总之，我们的研究证明，槲皮素通过抑制软骨细胞的炎症和凋亡、调节滑膜巨噬细胞向 M2 型极化以及为软骨细胞创造有利于软骨生成的环境来增强软骨修复，从而发挥软骨保护作用，在 OA 环境下。提示槲皮素可能成为治疗 OA 的潜在药物。
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