Lin Changjian, Ge Lujie, Tang Luping, He Yuzhe, Moqbel Safwat Adel Abdo, Xu Kai, Ma Diana, Zhou Xing, Ran Jisheng, Wu Lidong
Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Orthopedics Research Institute of Zhejiang University, Hangzhou, China.
Front Pharmacol. 2022 Jul 22;13:919940. doi: 10.3389/fphar.2022.919940. eCollection 2022.
Osteoarthritis (OA) is one of the most common chronic musculoskeletal disorder worldwide, representing a major source of disability, pain and socioeconomic burden. Yet the effective pharmaceutical treatments applied in the clinical works are merely symptomatic management with uncertainty around their long-term safety and efficacy, namely no drugs currently are capable of modulating the biological progression of OA. Here, we identified the potent anti-inflammatory as well as anti-oxidative properties of Nitidine Chloride (NitC), a bioactive phytochemical alkaloid extracted from natural herbs, in IL-1β-treated rat articular chondrocytes (RACs), LPS-stimulated RAW 264.7 and rat osteoarthritic models . We demonstrated NitC remarkably inhibited the production of inflammatory mediators including COX2 and iNOS, suppressed the activation of MAPK and NF-κB cell signaling pathway and reduced the expression of extracellular matrix (ECM) degrading enzymes including MMP3, MMP9 and MMP13 in IL-1β-treated RACs. Several emerging bioinformatics tools were performed to predict the underlying mechanism, the result of which indicated the potential reactive oxygen species (ROS) clearance potential of NitC. Further, NitC exhibited its anti-oxidative potential through ameliorating cellular senescence in IL-1β-treated RACs and decreasing NLRP3 inflammasomes activation in LPS-stimulated RAW 264.7 scavenging ROS. Additionally, X-ray, micro-CT and other experiments demonstrated that intra-articular injection of NitC significantly alleviated the cartilage erosion, ECM degradation and subchondral alterations in OA progression. In conclusion, the present study reported the potent anti-inflammatory and anti-oxidative potential of NitC in OA biological process, providing a promising therapeutic agent for OA management.
骨关节炎（OA）是全球最常见的慢性肌肉骨骼疾病之一，是导致残疾、疼痛和社会经济负担的主要原因。然而，临床应用的有效药物治疗仅仅是对症处理，其长期安全性和有效性存在不确定性，也就是说目前没有药物能够调节OA的生物学进程。在此，我们确定了从天然草药中提取的生物活性植物化学生物碱氯化两面针碱（NitC）在白细胞介素-1β处理的大鼠关节软骨细胞（RACs）、脂多糖刺激的RAW 264.7细胞和大鼠骨关节炎模型中具有强大的抗炎和抗氧化特性。我们证明，NitC在白细胞介素-1β处理的RACs中显著抑制包括COX2和iNOS在内的炎症介质的产生，抑制MAPK和NF-κB细胞信号通路的激活，并降低包括MMP3、MMP9和MMP13在内的细胞外基质（ECM）降解酶的表达。我们使用了几种新兴的生物信息学工具来预测潜在机制，结果表明NitC具有潜在的活性氧（ROS）清除能力。此外，NitC通过改善白细胞介素-1β处理的RACs中的细胞衰老以及减少脂多糖刺激的RAW 264.7细胞中NLRP3炎性小体的激活来清除ROS，从而发挥其抗氧化潜力。此外，X射线、显微CT等实验表明，关节内注射NitC可显著减轻OA进展过程中的软骨侵蚀、ECM降解和软骨下改变。总之，本研究报道了NitC在OA生物学过程中具有强大的抗炎和抗氧化潜力，为OA治疗提供了一种有前景的治疗药物。
