青藤碱对骨关节炎的治疗作用及机制探讨

doi:10.20047/j.issn1673-7210.2023.22.04

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摘要目的探讨青藤碱（SIN）对兔骨关节炎（OA）模型的治疗作用及机制。方法采用随机数字表法将15只体重在2.5～3.0 kg的普通级健康成年新西兰兔分为对照组、骨关节模型组（OA组）、青藤碱治疗组（SIN）组，每组5只。对照组应用生理盐水关节腔注射，OA组、SIN组分别用4%木瓜蛋白酶注射液和0.03 mol/L的L-半胱氨酸（2∶1）混合溶液以0.1 ml/kg关节腔内注射，分别于第1、4、7天共注射3次。造模2周后兔膝关节出现肿胀，活动障碍，造模成功。OA造模成功后SIN组给予盐酸SIN缓释片30 mg/（kg·d）灌胃，连续用药15 d，OA组、对照组不予特殊处理。4周后抽取兔血分别检测血清白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α），基质金属蛋白酶-1 （MMP-1）、MMP-13、Ⅱ型胶原（Collagen-Ⅱ）、软骨低聚物基质蛋白（COMP）水平，并行关节病理解剖学观察。取各组兔软骨组织行免疫组织化学检测软骨组织Collagen-Ⅱ、聚蛋白多糖及衰老相关基因p21、p53蛋白表达水平。结果 4周后OA组血清中IL-1β、TNF-α、MMP-1、MMP-13、Collagen-Ⅱ、COMP水平高于对照组（P＜0.05）；SIN组IL-1β、TNF-α、MMP-1、MMP-13、Collagen-Ⅱ、COMP水平低于OA组（P＜0.05）。大体标本观察显示：对照组关节正常，OA组关节腔有中等量关节积液，滑膜充血水肿，关节软骨面毛糙，而SIN组关节腔积液少，滑膜充血改善。镜下显示：与对照组比较，OA组兔膝关节软骨关节面不光滑，软骨明显变薄，滑膜大量炎症细胞浸润，滑膜增生、水肿明显；SIN组滑膜炎症细胞浸润及水肿、软骨损伤均较OA组减轻。免疫组织化学检测显示：OA组p21、p53表达水平高于对照组（P＜0.05），SIN组p21、p53表达低于OA组（P＜0.05）。聚蛋白多糖表达结果显示：OA组较对照组下降，SIN组较OA组表达增加。各组Ⅱ型胶原蛋白表达比较，差异无统计学意义（P＞0.05）。结论 SIN对OA有治疗作用，与抑制炎症因子及MMP分泌相关，并抑制软骨细胞衰老，为SIN用于OA治疗提供理论依据。

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	曹娟1　　姚瑶2　　李玲玲1　　陈晓琳1　　肖云云1　　武文卉1　　丁从珠1

关键词 ：骨关节炎, 青藤碱, 治疗机制, 细胞因子

Abstract：Objective To study the therapeutic effect and mechanism of sinomenine (SIN) on rabbit osteoarthritis (OA) model. Methods A total of 15 normal healthy adult New Zealand rabbits with body weight of 2.5-3.0 kg were randomly divided into control group, osteoarticular model group (OA group), and sinomenine treatment group (SIN group), with five rabbits in each group. The control group was injected with normal Saline in joint cavity, the OA group and SIN group were injected with a mixture of 4% Papain injection and 0.03 mol/L L-cysteine (2∶1) at 0.1 ml/kg intraarticular cavity, respectively. Three injections were given on the 1st, 4th and 7th day respectively. After two weeks of modeling, the knee joint of rabbits showed swelling and movement disturbance, and the modeling was successful, after OA modeling was successful, SIN group was given 30 mg/(kg·d) SIN Hydrochloride sustained-release tablets by intragastric administration, the drug was administered continuously for 15 days. No special treatment was given to OA group and control group. Serum levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-1 (MMP-1), MMP-13, Collagen Ⅱ, and cartilage oligomer matrix protein (COMP) were detected in rabbit blood samples after four weeks. Joint pathological anatomy was observed. The expression levels of Collagen Ⅱ, polyproteoglycan and aging-related genes p21 and p53 were detected by immunohistochemistry in rabbit cartilage tissues of each group. Results After four weeks, the serum levels of IL-1β, TNF-α, MMP-1, MMP-13, Collagen Ⅱ, and COMP in OA group were higher than those in control group (P＜0.05); the levels of IL-1β, TNF-α, MMP-1, MMP-13, Collagen Ⅱ, and COMP in SIN group were lower than those in OA group (P＜0.05). Gross specimen observation showed that the joints of the control group were normal, the joint cavity of the OA group had an equal amount of joint effusion, synovial edema, and rough articular cartilage surface, while the joint cavity of the SIN group had less effusion and improved synovial congestion. Compared with the control group, the articular surface of the knee cartilage in OA group was not smooth, the cartilage was obviously thinner, the synovial membrane was infiltrated by a large number of inflammatory cells, and the synovial membrane hyperplasia and edema were obvious, the infiltration of synovial inflammatory cells, edema, and cartilage injury in SIN group were less than those in OA group. Immunohistochemical detection showed that the expression levels of p21 and p53 in OA group were higher than those in control group (P＜0.05), and the expressions of p21 and p53 in SIN group were lower than those in OA group (P＜0.05). The expression of polyproteoglycan in OA group was lower than that in control group, and the expression in SIN group was higher than that in OA group. There were no significant differences in the expression of type Ⅱ collagen among all groups (P＞0.05). Conclusion SIN has a therapeutic effect on OA, which is related to inhibiting the secretion of inflammatory factors and MMP, and inhibiting the senescence of chondrocytes, providing a theoretical basis for the use of SIN in OA treatment.

Key words： Osteoarthritis Sinomenine Therapeutic mechanism Cytokines

基金资助:江苏省卫生健康委员会科研课题（BJ19003）；
江苏省南京市卫生和计划生育委员会医学科技发展项目（ZKX17020）。

通讯作者: 丁从珠（1962-），女，博士，博士生导师，主任医师；研究方向：老年风湿免疫学。

作者简介: 曹娟（1978-），女，硕士，副主任医师；研究方向：老年骨关节炎。

引用本文:

曹娟1　　姚瑶2　　李玲玲1　　陈晓琳1　　肖云云1　　武文卉1　　丁从珠1. 青藤碱对骨关节炎的治疗作用及机制探讨[J]. 中国医药导报, 2023, 20(22): 18-23.
CAO Juan1 YAO Yao2 LI Lingling1 CHEN Xiaolin1 XIAO Yunyun1 WU Wenhui1 DING Congzhu1. Discuss on the therapeutic effect and mechanism of sinomenine on osteo-arthritis. 中国医药导报, 2023, 20(22): 18-23.

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