Guo Qianyu, Liang Meie, Li Zhen, Li Jie, Xu Ke, Zhang Liyun
Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China.
Department of Rheumatology, Taiyuan, China.
Front Immunol. 2025 Aug 27;16:1646918. doi: 10.3389/fimmu.2025.1646918. eCollection 2025.
The occurrence and development of rheumatoid arthritis (RA) are closely related to bone erosion caused by the abnormal activation of the Wnt3a/β-catenin signaling pathway. However, it remains unclear how natural products target and regulate this pathway at the molecular level. This study focuses on the role of the novel neuronal guidance protein NAV2 in RA and systematically analyzes the immunoregulatory mechanism of matrine (MAT).
A Wistar rat model of type II collagen-induced arthritis (CIA) was established by co-induction with bovine type II-collagen and Freund's adjuvant. Twenty-four rats were randomly divided into four groups in total: a normal control group (NOR), a model group (CIA), a methotrexate treatment group (MTX), and a matrine treatment group (MAT). Intragastric administration was carried out over four weeks.Ankle bone mineral density (BMD), trabecular thickness (tb.th) and other related indicators were detected. The dynamic balance of serum inflammatory factors was measured via enzyme-linked immunosorbent assay (ELISA). The destruction of articular bone was gauged utilizing three-dimensional reconstruction with Micro-CT. Hematoxylin and eosin (HE) staining, along with O-fast green staining, were employed to appraise synovial inflammation and the degree of cartilage damage in the joints. qRT-PCR and Western blotting were utilized to detect the mRNA and protein expression levels of NAV2, Wnt3a, and β-catenin in rat joints.
MAT remarkably decreased the arthritis index in CIA rats (p<0.01), and effectively ameliorated articular bone erosion and synovial inflammatory infiltration. MAT systematically reduced the levels of pro-inflammatory cytokines, while increasing the levels of anti-inflammatory cytokines. No significant statistical differences were observed in liver and kidney function between the MAT group and NOR group (p>0.05). MAT significantly inhibited the mRNA and protein expressions of NAV2, Wnt3a, and β-catenin in joints (all p<0.05). Following intervention with MAT, there was a significant decrease in the positive areas of these three molecules (p<0.01).
Through the targeted inhibition of the NAV2-Wnt3a/β-catenin signal transduction pathway, MAT exerts a dual-regulatory effect to restore the equilibrium of the inflammatory cytokine network. Moreover, MAT demonstrates no hepatotoxicity or nephrotoxicity, thereby providing a novel candidate molecule and a mechanistic target for the intervention of autoimmune diseases using natural drugs.
类风湿关节炎（RA）的发生发展与Wnt3a/β-连环蛋白信号通路异常激活所导致的骨侵蚀密切相关。然而，天然产物如何在分子水平靶向调控该通路仍不清楚。本研究聚焦新型神经元导向蛋白NAV2在RA中的作用，并系统分析苦参碱（MAT）的免疫调节机制。
通过牛Ⅱ型胶原蛋白与弗氏佐剂联合诱导建立Wistar大鼠Ⅱ型胶原诱导性关节炎（CIA）模型。24只大鼠共随机分为四组：正常对照组（NOR）、模型组（CIA）、甲氨蝶呤治疗组（MTX）和苦参碱治疗组（MAT）。进行四周的灌胃给药。检测踝关节骨密度（BMD）、骨小梁厚度（tb.th）等相关指标。通过酶联免疫吸附测定（ELISA）检测血清炎症因子的动态平衡。利用Micro-CT三维重建评估关节骨破坏情况。采用苏木精-伊红（HE）染色及固绿染色评估滑膜炎症及关节软骨损伤程度。运用qRT-PCR和蛋白质印迹法检测大鼠关节中NAV2、Wnt3a和β-连环蛋白的mRNA和蛋白表达水平。
MAT显著降低CIA大鼠的关节炎指数（p<0.01），并有效改善关节骨侵蚀和滑膜炎症浸润。MAT系统性降低促炎细胞因子水平，同时提高抗炎细胞因子水平。MAT组与NOR组之间的肝肾功能无显著统计学差异（p>0.05）。MAT显著抑制关节中NAV2、Wnt3a和β-连环蛋白的mRNA和蛋白表达（均p<0.05）。MAT干预后，这三种分子的阳性面积显著减少（p<0.01）。
MAT通过靶向抑制NAV2-Wnt3a/β-连环蛋白信号转导通路发挥双重调节作用，以恢复炎症细胞因子网络的平衡。此外，MAT无肝毒性或肾毒性，从而为使用天然药物干预自身免疫性疾病提供了一种新的候选分子及作用机制靶点。
