实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (3): 259-268.DOI: 10.12300/j.issn.1674-5817.2024.165
刘智伟, 杨然, 连浩, 张玉, 金立伦(
)(
)
收稿日期:2024-11-08
修回日期:2025-02-07
出版日期:2025-07-07
发布日期:2025-06-25
通讯作者:
金立伦（1967—），男，硕士，主任医师，研究方向：膝骨关节炎的发病机制与中药干预。E-mail：jinlilun@xinhuamed.com.cn。ORCID：0000-0001-9840-836X作者简介:刘智伟（1997—），男，硕士研究生，研究方向：膝骨关节炎的发病机制与中药干预。E-mail：rickyliu13@163.com
基金资助:
LIU Zhiwei, YANG Ran, LIAN Hao, ZHANG Yu, JIN Lilun()()
Received:2024-11-08
Revised:2025-02-07
Published:2025-06-25
Online:2025-07-07
Contact:
JIN Lilun (ORCID: 0000-0001-9840-836X), E-mail: jinlilun@xinhuamed.com.cn摘要：
目的 建立大鼠骨关节炎模型，研究秦皮素对骨关节炎大鼠的抗炎作用及机制。 方法 18只8周龄雄性SPF级SD大鼠随机分为3组：空白组大鼠右膝关节腔注射50 μL生理盐水并连续1周；模型组和干预组大鼠右膝关节腔注射碘乙酸钠（monosodium iodoacetate，MIA）造模，干预组再注射秦皮素（5 mg·kg-1·d-1）并连续干预1周。药物干预后4周，采集腹主动脉血，安乐死动物后采集膝关节软骨。采用苏木精-伊红染色、番红O-固绿染色和甲苯胺蓝染色进行膝关节软骨的组织病理学观察以及Mankin和OARSI评分，并用micro-CT扫描系统比较分析每组膝关节的骨体积分数、骨表面积密度和骨小梁数目。采用酶联免疫吸附试验法检测各组大鼠血清中多种炎症因子［肿瘤坏死因子α（tumor necrosis factor-α，TNF-α）、白细胞介素1β（interleukin-1β，IL-1β）、白细胞介素6（interleukin-6，IL-6）］以及软骨寡聚基质蛋白（cartilage oligomeric matrix protein，COMP）的表达。采用蛋白质印迹法测定膝关节软骨中丝裂原活化蛋白激酶p38（mitogen-activated protein kinase p38，p38 MAPK）、磷酸化丝裂原活化蛋白激酶p38（phosphorylation-p38 MAPK，p-p38 MAPK）、c-Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）、磷酸化JNK氨基末端激酶（phosphorylation-JNK，p-JNK）的表达。 结果 大鼠膝关节软骨切片染色显示，模型组的关节面缺损严重，干预组的软骨破坏相对减轻。micro-CT显示，干预组的骨体积分数、骨表面积密度和骨小梁数目均明显高于模型组（P＜0.05）；模型组的Mankin评分明显高于空白组（P＜0.05），干预组的Mankin评分明显低于模型组（P＜0.05）；而干预组的OARSI评分明显低于模型组（P＜0.05）。酶联免疫吸附试验结果显示，模型组大鼠血清中TNF-α、IL-1β、IL-6和COMP含量均明显高于空白组（均P＜0.05），而干预组含量明显低于模型组（均P＜0.05）。蛋白质印迹结果显示，干预组膝关节软骨组织中p-p38 MAPK和p-JNK表达水平明显低于模型组（均P＜0.05），而模型组的p-p38 MAPK和p-JNK蛋白表达水平明显高于空白组（均P＜0.05）。 结论 秦皮素药物干预可能通过p38 MAPK通路对碘乙酸钠诱导的骨关节炎模型大鼠发挥治疗作用。
中图分类号:
刘智伟,杨然,连浩,等. 秦皮素对碘乙酸钠诱导骨关节炎模型大鼠的软骨保护与抗炎作用[J]. 实验动物与比较医学, 2025, 45(3): 259-268. DOI: 10.12300/j.issn.1674-5817.2024.165.
LIU Zhiwei,YANG Ran,LIAN Hao,et al. Cartilage Protection and Anti-Inflammatory Effects of Fraxetin on Monosodium Iodoacetate-Induced Rat Model of Osteoarthritis[J]. Laboratory Animal and Comparative Medicine, 2025, 45(3): 259-268. DOI: 10.12300/j.issn.1674-5817.2024.165.
图1 碘乙酸钠注射造模及秦皮素药物干预后大鼠膝关节软骨组织病理学变化注：A、B、C分别为3组大鼠膝关节软骨组织的苏木精-伊红、番红O-固绿、甲苯胺蓝染色结果（比例尺为300 μm，黑色箭头指向膝关节软骨表面）。空白组指先向右膝关节腔注射50 μL生理盐水，再腔内连续7 d注射50 μL 生理盐水的大鼠；模型组指右膝关节腔内单次注射50 μL新鲜配制的（60 mg/mL）碘乙酸钠建立膝骨关节炎动物模型，再连续7 d注射50 μL 生理盐水的大鼠；干预组指右膝关节腔内单次注射50 μL新鲜配制的（60 mg/mL）碘乙酸钠后，再连续7 d每天注射5 mg/kg秦皮素（溶于50 μL 生理盐水）的大鼠。
Figure 1 Histopathological changes in rat knee joint cartilage after monosodium iodoacetate injection and fraxetin interventionNote： A， B， and C are the staining results of hematoxylin-eosin， safranin O–fast green， and toluidine blue in the knee cartilage tissue of three groups of rats （scale bar = 300 μm， the black arrow in the picture points to the surface of the knee cartilage）. The blank group refers to rats that were first injected with 50 μL of normal saline into the right knee joint cavity， followed by intra-articular injections of 50 μL of normal saline for 7 consecutive days； the model group refers to rats that were injected with one time injection of 50 μL fresh prepared monosodium iodoacetate （60 mg/mL）in the right knee joint cavity to induce osteoarthritis， followed by injections of 50 μL of normal saline for 7 consecutive days； the intervention group refers to rats that were injected with one time injection of 50 μL fresh prepared monosodium iodoacetate （60 mg/mL）in the right knee joint cavity， followed by fraxetin injections （5 mg·kg-1·d-1， dissolved in 50 μL of normal saline） for 7 consecutive days.
分组 Group | 动物数量 n | Mankin评分 Mankin score | OARSI评分 OARSI sore | 骨体积分数 Tb.BV/TV | 骨表面积密度/(mm2·mm-3) Tb.BS/TV | 骨小梁数量/mm-1 Tb.N |
|---|---|---|---|---|---|---|
| 空白组 Blank group | 6 | 1.17±0.75 | 1.83±0.75 | 0.59±0.01 | 17.44±0.60 | 3.72±0.21 |
| 模型组 Model group | 6 | 10.67±1.86* | 8.00±1.41* | 0.25±0.02* | 13.28±0.86* | 2.47±0.19* |
| 干预组 Intervention group | 6 | 5.67±0.82# | 5.50±1.05# | 0.38±0.02# | 15.59±0.50# | 3.29±0.14# |
表1 不同组大鼠膝关节软骨的Mankin评分、OARSI评分、骨体积分数、骨表面积密度、骨小梁数量比较
Table 1 Comparison of Mankin score, OARSI score, Tb.BV/TV, Tb.BS/TV, and Tb.N of knee cartilage among different groups
分组 Group | 动物数量 n | Mankin评分 Mankin score | OARSI评分 OARSI sore | 骨体积分数 Tb.BV/TV | 骨表面积密度/(mm2·mm-3) Tb.BS/TV | 骨小梁数量/mm-1 Tb.N |
|---|---|---|---|---|---|---|
| 空白组 Blank group | 6 | 1.17±0.75 | 1.83±0.75 | 0.59±0.01 | 17.44±0.60 | 3.72±0.21 |
| 模型组 Model group | 6 | 10.67±1.86* | 8.00±1.41* | 0.25±0.02* | 13.28±0.86* | 2.47±0.19* |
| 干预组 Intervention group | 6 | 5.67±0.82# | 5.50±1.05# | 0.38±0.02# | 15.59±0.50# | 3.29±0.14# |
图2 碘乙酸钠注射造模及秦皮素药物干预后大鼠膝关节的micro-CT成像注：A、B、C、D分别从膝关节3D层面、胫骨平台、软骨下骨水平面以及横截面特定区域截面扫描3组大鼠膝关节，观察相关骨质情况，评价骨关节炎情况。空白组指先向右膝关节腔注射50 μL生理盐水，再腔内连续7 d注射50 μL生理盐水的大鼠；模型组指右膝关节腔内单次注射50 μL新鲜配制的60 mg/mL碘乙酸钠建立膝骨关节炎动物模型，再连续7 d注射50 μL生理盐水的大鼠；干预组指右膝关节腔内单次注射50 μL新鲜配制的60 mg/mL碘乙酸钠后，再连续7 d每天注射5 mg/kg秦皮素（溶于50 μL生理盐水）的大鼠。
Figure 2 Micro-CT imaging of the rat knee joint after monosodium iodoacetate injection and fraxetin treatmentNote： A， B， C， and D represent micro-CT images of the knee joints of three groups of rats， scanned at the levels of 3D reconstruction， the tibial platform， the subchondral bone， and specific cross-sectional regions， to assess bone structure and evaluate osteoarthritis changes. The blank group refers to rats that were first injected with 50 μL of normal saline into the right knee joint cavity， followed by intra-articular injections of 50 μL of normal saline for 7 consecutive days； the model group refers to rats that were injected with one time injection of 50 μL fresh prepared monosodium iodoacetate （60 mg/mL）in the right knee joint cavity to induce osteoarthritis， followed by injection of 50 μL of normal saline for 7 consecutive days； the intervention group refers to rats that were injected with one time injection of 50 μL fresh prepared monosodium iodoacetate （60 mg/mL）in the right knee joint cavity， followed by intra-articular injections of fraxetin （5 mg·kg-1·d-1， dissolved in 50 μL of normal saline） for 7 consecutive days.
图3 秦皮素药物干预后大鼠血清和膝关节软骨组织中炎症相关蛋白的表达注：A～D分别为ELISA法检测各组大鼠血清IL-6、IL-1β、TNF-α、COMP含量变化。E为蛋白质印迹法检测各组大鼠膝关节软骨组织中p38 MAPK、JNK、p-p38 MAPK、p-JNK蛋白表达。F、G为p-JNK/JNK、p-p38 MAPK/p38 MAPK蛋白表达量比值（反映JNK、p38磷酸化程度，代表通路激活程度）。空白组指先向右膝关节腔注射50 μL生理盐水，再腔内连续7 d注射50 μL 生理盐水的大鼠；模型组指右膝关节腔内单次注射50 μL新鲜配制的60 mg/mL碘乙酸钠建立膝骨关节炎动物模型，再连续7 d注射50 μL生理盐水的大鼠；干预组指右膝关节腔内单次注射50 μL新鲜配制的60 mg/mL碘乙酸钠后，再连续7 d每天注射5 mg/kg秦皮素（溶于50 μL生理盐水）的大鼠。每组6只大鼠（n=6），与空白组相比，*P＜0.05；与模型组相比，#P＜0.05。
Figure 3 Expression of inflammation-related proteins in rat serum and knee cartilage after fraxetin treatmentNote： A-D， show the serum levels of IL-6， IL-1β， TNF-α， and COMP detected by ELISA. E shows the expression of p38 MAPK， JNK， p-p38 MAPK， and p-JNK proteins in knee cartilage tissues detected by Western blotting. F and G show the ratios of p-JNK/JNK and p-p38 MAPK/p38 MAPK， reflecting the phosphorylation levels of JNK and p38， which indicate the activation levels of the corresponding pathways. The blank group refers to rats that were first injected with 50 μL of normal saline into the right knee joint cavity， followed by intra-articular injections of 50 μL of normal saline for 7 consecutive days； the model group refers to rats that were injected with one time injection of 50 μL fresh prepared monosodium iodoacetate （60 mg/mL）in the right knee joint cavity to induce osteoarthritis， followed by intra-articular injections of 50 μL of normal saline for 7 consecutive days； the intervention group refers to rats that were injected with one time injection of 50 μL fresh prepared monosodium iodoacetate （60 mg/mL）in the right knee joint cavity， followed by intra-articular injections of fraxetin （5 mg·kg-1·d-1， dissolved in 50 μL of normal saline） for 7 consecutive days. There were 6 rats in each group （n=6）. Compared with the blank group， *P<0.05； compared with the model group， #P<0.05.
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