SIRT1-FOXO1-TLR4-NF-kappaB信号级联反应在白藜芦醇抗骨性关节炎中的作用

Systemic inflammation associated with obesity is a major risk factor for osteoarthritis (OA). Therefore, to explore the mechanisms of OA in obesity-associated systemic inflammation as well as to find the effective intervention target/measure is an important strategy for OA management. Here, we discuss the effects of a natural polyphenol-resveratrol on a mice model of obesity-induced OA with high-fat diet and on mice and human articular chondrocytes in vitro with an emphasis on molecular antiosteoarthritic mechanisms. It is demonstrated that in chondrocytes, SIRT1-FOXO1-TLR4-NF-kappaB signaling cascade is at least one major mechanism for the antiosteoarthritis effect of resveratrol. We show that resveratrol can activates SIRT1, upregulation of the latter activates FOXO1 by deacetylating and subsequently potentiates the negative feedback of FOXO1-TLR4-Akt axis in the context of chronic low-grade inflammation, resulting to TLR4 inhibition and subsequent inactivation of NF-kappaB, which alleviates the inflammatory state in chondrocytes of OA. In addition, we also follow up the curative effect of resveratrol on OA patients in early clinical stage. Thus, the study might provide not only basic mechanisms but also clinical data for the intervention target and nutrition therapy for OA.

肥胖有关的系统性炎症是骨性关节炎（osteoarthritis, OA）发生发展的主要危险因素，探讨与肥胖有关的系统性炎症在OA发生发展中的作用机制并寻找有效的干预靶点及措施是治疗OA的重要策略。本项目首先通过建立高脂膳食诱导的肥胖OA小鼠模型，观察天然多酚类化合物白藜芦醇抗OA的效应并通过C57BL/6J小鼠和人软骨细胞体外培养探讨其作用机制，推测白藜芦醇可通过SIRT1-FOXO1-TLR4-NF-kappaB信号级联反应发挥抗OA效应，即白藜芦醇激活SIRT1，增加的SIRT1使FOXO1去乙酰化而活化，进而增强肥胖低度炎症状态下FOXO1-TLR4-Akt轴的负反馈作用，导致TLR4降低，引起NF-kappaB失活，从而改善OA软骨细胞的炎症状态； 然后将白藜芦醇用于临床早期OA患者，观察其疗效，为寻找有效的OA干预靶点及营养干预措施提供基础和临床资料。

肥胖是骨性关节炎（osteoarthritis, OA）发生发展的主要危险因素，探讨肥胖相关OA的作用机制并寻找有效的干预措施是防治OA的重要策略。本项目通过采用白藜芦醇干预高脂膳食诱导的肥胖OA小鼠的动物实验，以及采用OA患者的软骨细胞及人SW1353软骨肉瘤细胞系的体外实验研究，明确了白藜芦醇抗肥胖相关OA的效应，揭示了可能的作用机制，证明（1）白藜芦醇通过增强软骨细胞中TLR4-Akt-FOXO1轴的负反馈作用，即白藜芦醇作用于PI3K/Akt信号通路，而活化的Akt可引起FOXO1的磷酸化而致其失活，失活的FOXO1导致TLR4表达下降，进而通过抑制TLR4/MyD88依赖性及非依赖性信号通路，引起NF-κB失活，从而改善OA软骨细胞的炎症状态；（2）白藜芦醇可以诱导FOXO1依赖的SIRT1的表达，SIRT1可能通过直接或间接作用抑制TLR4/NF-κB信号通路，发挥抗OA效应。最后，本项目通过病例-对照研究，对OA常见影响因素（尤其是膳食因素）进行调查，揭示肉类、坚果类是OA的保护因素，而饮用酒是OA的危险因素。本项目对阐明肥胖相关OA的发病机制及探索营养干预措施具有重要价值，而白藜芦醇作为一种天然的植物化学物，具有潜在的临床应用前景。