Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325088, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopedics, Wenzhou 325035, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325088, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopedics, Wenzhou 325035, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
Int Immunopharmacol. 2024 Nov 15;141:112960. doi: 10.1016/j.intimp.2024.112960. Epub 2024 Aug 18.
Osteoarthritis (OA) is the predominant cause of disability among elderly people worldwide and is characterized by cartilage degeneration and excessive bone formation. Phillyrin, derived from forsythia, is a key extract renowned for its pronounced antibacterial and anti-inflammatory effects. Forsythia, deeply integrated into traditional Oriental medicine, has historically been utilized for its various pharmacological effects, including antibacterial, anti-inflammatory, and hepato-protective properties. Nevertheless, the anti-inflammatory impact of phillyrin on the progression of osteoarthritis remains enigmatic. The objective of this research was to assess the anti-inflammatory and anti-aging properties of phillyrin in mouse chondrocytes induced by IL-1β, as well as to elucidate the fundamental mechanisms underlying the phenomenon at play. Additionally, the investigation extends to observing the impact of phillyrin by establishing a murine osteoarthritic model. The ultimate goal was to identify phillyrin as a potential antiosteoarthritic agent. This investigation employs a multifaceted approach. Initially, key action targets of phillyrin, along with its probable action pathways, were identified by molecular docking and network pharmacological techniques. These findings were subsequently confirmed through both in vivo and in vitro studies. Network pharmacological analysis revealed NFE2L2 (NRF2), NFKB1, TLR4, and SERPING1 as pivotal candidate targets for the treatment of osteoarthritis with phillyrin. Molecular docking revealed hydrogen bond interactions between phillyrin and Arg415, Arg483, Ser508, and Asn387 on the Nrf2 receptor, while electrostatic interactions occurred with residues Arg415 and Arg380. Experiments conducted in vitro indicated that phillyrin preconditioning hindered the IL-1β-induced expression of proinflammatory factors which included TNF-α, COX-2, IL-6, and iNOS. Furthermore, phillyrin counteracts the IL-1β-induced degradation of aggrecan and collagen II within the extracellular matrix (ECM). This protective action is caused by the inhibition of the NF-κB pathway by phillyrin. Additionally, the mitigation of chondrocyte aging by phillyrin was observed. Our investigation revealed that phillyrin mitigates inflammation and counteracts cartilage degeneration in osteoarthritis (OA) patients by suppressing inflammation in chondrocytes and impeding aging through suppression of the NF-κB pathway.
骨关节炎（OA）是全球老年人致残的主要原因，其特征是软骨退化和过度骨形成。连翘苷源自连翘，是一种具有显著抗菌和抗炎作用的关键提取物。连翘在传统东方医学中有着深厚的根基，历史上一直因其多种药理学作用而被应用，包括抗菌、抗炎和保肝作用。然而，连翘苷在骨关节炎进展中的抗炎作用仍然是个谜。本研究旨在评估 IL-1β诱导的小鼠软骨细胞中连翘苷的抗炎和抗衰老特性，并阐明其发挥作用的基本机制。此外，通过建立鼠骨关节炎模型来观察连翘苷的影响。最终目标是确定连翘苷作为一种潜在的抗骨关节炎药物。本研究采用了多方面的方法。首先，通过分子对接和网络药理学技术，确定了连翘苷的关键作用靶点及其可能的作用途径。这些发现随后通过体内和体外研究得到了证实。网络药理学分析表明，NFE2L2（NRF2）、NFKB1、TLR4 和 SERPING1 是连翘苷治疗骨关节炎的关键候选靶点。分子对接显示，连翘苷与 Nrf2 受体上的 Arg415、Arg483、Ser508 和 Asn387 之间存在氢键相互作用，而与 Arg415 和 Arg380 之间存在静电相互作用。体外实验表明，连翘苷预处理可抑制 IL-1β诱导的 TNF-α、COX-2、IL-6 和 iNOS 等促炎因子的表达。此外，连翘苷可对抗细胞外基质（ECM）中聚集蛋白聚糖和胶原 II 的降解。这种保护作用是由连翘苷抑制 NF-κB 通路引起的。此外，还观察到连翘苷可减轻软骨细胞衰老。我们的研究表明，连翘苷通过抑制软骨细胞炎症和 NF-κB 通路，减轻炎症和对抗软骨退化，从而减轻骨关节炎（OA）患者的炎症和对抗软骨退化。
