Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321#, 210008 Nanjing, China.
Department of Pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321#, 210008 Nanjing, China.
Int Immunopharmacol. 2014 Jan;18(1):135-41. doi: 10.1016/j.intimp.2013.11.014. Epub 2013 Nov 25.
OBJECTIVE: To analyze the combination therapy of Sinomenine (SIN) and Methotrexate (MTX) in rheumatoid arthritis (RA), we herein demonstrated the combination effect of SIN and MTX on collagen-induced arthritis (CIA) in rats through their modulation on osteoclast-related cytokines. METHODS: CIA was induced by the immunization of type II collagen (CII) in SD rats. SIN and MTX were administrated alone or in combination after the onset of arthritis. Arthritis index and histological analysis were used to evaluate the effect of treatments. Effects of SIN and MTX on expression of receptor activator of NF-κB ligand (RANKL) and osteopontin (OPN) in synovial tissues were assayed by immunohistochemistry. RANKL, osteoprotegerin (OPG), IL-6, IL-17 and matrix metalloproteinases (MMPs) in rat serum were measured by ELISA. The expression of osteoclast-related cytokines in fibroblast-like synoviocytes (FLS) from RA patients was assayed by RT-PCR. RESULTS: SIN and MTX combination additively reduced the inflammatory symptoms and joint damage in CIA. Combination of SIN and MTX significantly repressed synovial RANKL and OPN production. SIN and MTX exhibited complementary and synergistic effect upon down-regulating RANKL, IL-6, IL-17 and MMPs in rat serum. SIN and MTX also modulated the expression of RANKL and OPG in RA-FLS. CONCLUSION: SIN and MTX have additive effects, decreasing inflammation and joint damage in CIA rats by modulating osteoclast-related cytokines. These results are indicative of the combined effect of SIN and MTX for anti-arthritic treatment in RA.
目的：通过分析青藤碱（SIN）和甲氨蝶呤（MTX）联合治疗类风湿关节炎（RA）的疗效，本研究旨在探讨 SIN 和 MTX 对胶原诱导性关节炎（CIA）大鼠的联合作用及其对破骨细胞相关细胞因子的调节作用。
方法：采用 II 型胶原（CII）免疫 SD 大鼠诱导 CIA，关节炎发病后单独或联合给予 SIN 和 MTX 治疗。采用关节炎指数和组织学分析评估治疗效果。免疫组化法检测滑膜组织中核因子-κB 受体激活因子配体（RANKL）和骨桥蛋白（OPN）的表达。酶联免疫吸附试验（ELISA）检测大鼠血清中 RANKL、骨保护素（OPG）、白细胞介素-6（IL-6）、白细胞介素-17（IL-17）和基质金属蛋白酶（MMPs）的水平。采用 RT-PCR 检测 RA 患者成纤维样滑膜细胞（FLS）中破骨细胞相关细胞因子的表达。
结果：SIN 和 MTX 联合应用可显著减轻 CIA 大鼠的炎症症状和关节损伤。联合应用 SIN 和 MTX 可显著抑制滑膜组织 RANKL 和 OPN 的产生。SIN 和 MTX 对 RANKL、IL-6、IL-17 和 MMPs 的下调作用具有互补和协同作用。SIN 和 MTX 还可调节 RA-FLS 中 RANKL 和 OPG 的表达。
结论：SIN 和 MTX 具有相加作用，通过调节破骨细胞相关细胞因子，减轻 CIA 大鼠的炎症和关节损伤。这些结果提示 SIN 和 MTX 联合应用可能对 RA 的抗关节炎治疗具有协同作用。
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