基于线粒体-内质网稳态的天然产物干预膝骨关节炎的机制研究进展

Research progress on the mechanism of natural products based on mitochondrial endoplasmic reticulum homeostasis in the intervention of knee osteoarthritis

关键词:  膝骨关节炎  天然产物  炎症  氧化应激  线粒体  内质网

Key words:  knee osteoarthritis  natural products  inflammation  oxidative stress  mitochondria  endoplasmic reticulum

摘要:

膝骨关节炎（KOA）是中老年人最常见的退行性关节疾病，其病理过程涉及软骨退变、滑膜炎症、软骨下骨重塑异常及关节内微环境失衡。近年来，大量研究表明炎症反应、氧化应激、线粒体功能障碍以及线粒体-内质网膜接触稳态异常在KOA发生发展中发挥关键作用。上述机制之间存在广泛的信号交叉，形成“炎症-氧化应激-能量代谢失衡”的恶性循环，加速软骨细胞衰老与凋亡。天然产物因其结构多样性、多靶点、低毒性及良好的代谢调控能力，在KOA的防治中展现出独特优势。多种黄酮类、多酚类、生物碱及三萜类天然产物可通过抑制核因子-κB和丝裂原活化蛋白激酶（NF-κB/MAPK）信号、降低炎症因子，激活核因子E2相关因子2和抗氧化反应元件（Nrf2/ARE）通路、维持线粒体功能、促进线粒体自噬以及调控线粒体-内质网膜接触稳态改善KOA。综述系统归纳KOA的核心病理机制，并基于近年来动物实验及细胞研究，重点阐述天然产物通过调控炎症反应、氧化应激、线粒体功能与线粒体-内质网膜接触稳态改善KOA的作用机制，提出未来研究方向，为开发新型天然产物抗KOA药物提供理论依据。

Abstract:

Knee osteoarthritis（KOA） is one of the most prevalent degenerative joint disorders among the elderly. Its pathological progression is characterized by articular cartilage destruction，synovial inflammation，subchondral bone remodeling，and disruption of the intra-articular microenvironment. Emerging evidence has highlighted the central roles of inflammatory responses，oxidative stress，mitochondrial dysfunction，and dysregulation of mitochondria-associated endoplasmic reticulum membranes（MAMs） in KOA development. Crosstalk among these mechanisms forms a vicious cycle of “inflammation-oxidative stress-energy metabolism imbalance”，accelerating chondrocyte senescence and apoptosis. Natural products-particularly flavonoids，polyphenols，terpenoids，and alkaloids-exert multi-target actions and exhibit strong anti-inflammatory，antioxidant，and mitochondrial-protective effects. Increasing studies show that natural products can modulate NF-κB/MAPK signaling，activate the Nrf2/ARE pathway，restore mitochondrial function，promote mitophagy，and potentially regulate MAMs homeostasis to alleviate KOA. This review provides a systematic summary of the core pathological mechanisms of KOA and elaborates on the molecular mechanisms by which natural products modulate inflammation，oxidative stress，mitochondrial homeostasis，and MAMs function. Future research directions are proposed to support the development of new natural-product-based therapeutics for KOA.