怀牛膝对兔骨性关节炎软骨组织影响的实验研究
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摘要
目的
观察骨关节炎模型兔膝关节软骨组织的病理生理变化,探讨怀牛膝对骨关节炎模型兔膝关节软骨组织的作用机制,为中医药防治骨性关节炎的实验研究与临床应用提供一些依据。
方法
新西兰大白兔随机分为正常组、模型组、治疗组(怀牛膝)、对照组(西乐葆),其中治疗组分为怀牛膝高剂量、中剂量和低剂量三组。参照Hulth造模法制作实验性兔骨关节炎模型。造模一周后开始给药,连续治疗6周后取材,分别检测病灶软骨组织形态及病理生理学相关因子的变化,具体分四个部分：
1采用组织化学法制备软骨组织标本及切片,在光镜和电镜下观察病灶软骨组织形态学变化。
2在切开病灶膝关节之前抽取关节液,采用化学比色法检测关节液中NOS、SOD的含量。
3运用免疫印迹法分别检测滑膜组织中MMP-3、MMP-13、TIMP-1表达,通过图像分析系统比较各组之间差异。
4运用免疫组织化学技术分别检测软骨组织IGF-1和II型胶原,通过图像分析系统比较各组之间差异。
结果
1组织形态学变化：正常组关节软骨组织表层光滑、平整,软骨细胞分布均匀；模型组软骨组织表层明显变薄甚至消失,可见细胞簇集,软骨细胞排列紊乱；治疗组中怀牛膝高、中剂量组和对照组软骨组织破坏程度明显减轻,少数区域可见软骨细胞排列不规则；怀牛膝低剂量组和模型组差别不大。各组软骨组织评分中模型组较正常组评分明显升高(P<0.01)；怀牛膝高、中剂量组和对照组较模型组显著降低(P<0.01)；怀牛膝高、中剂量组组间比较无明显差异,但分别较对照组存在差异；怀牛膝低剂量组与模型组之间差异不明显(P>0.05)。电镜下观察正常组软骨细胞基本正常；模型组软骨细胞外形不规则,软骨细胞有固缩现象；怀牛膝高、中剂量组软骨细胞轻度异常,部分出现空泡,胞浆内细胞器增多；且细胞损伤程度好于对照组和怀牛膝低剂量组。
2关节液中NOS含量模型组较正常组明显升高(P<0.01)；怀牛膝高、中剂量和对照组较模型组均明显降低(P<0.01),且对照组和怀牛膝高剂量组NOS含量低于中剂量组；怀牛膝低剂量组与模型组间无明显差异(P>0.05)。关节液中SOD含量模型组较正常组明显降低(P<0.01)；怀牛膝高剂量组SOD含量高于中剂量,且两组均比模型组明显升高(P<0.01),低剂量组和对照组与模型组比较差异不明显(P>0.05)。
3病灶侧滑膜组织中MMP-3和MMP-13在治疗组中怀牛膝高、中剂量组和对照组之间差异不明显(P>0.05),三组与模型组之间比较差异明显(P<0.01);TIMP-1数值在怀牛膝高、中剂量组和对照组与模型组比较均差异显著(P<0.01)；而怀牛膝高、中剂量组较对照组也存在差异(P<0.05)；怀牛膝低剂量组MMP-3、MMP-13和TIMP-1数值与模型组间无明显差异(P>0.05)。
4病变组织中IGF-1表达怀牛膝高剂量组高于中剂量组(P<0.01),且两组均明显高于对照组、怀牛膝低剂量组和模型组(P<0.01)。病变组织中II胶原的表达,怀牛膝高、中剂量组和对照组与模型组比较差异明显(P<0.01),且高、中剂量组好于对照组(P<0.05)；低剂量组与模型组比较无差异(P>0.05)。
结论
怀牛膝有延缓OA模型中软骨组织退变的作用,且相对与西乐葆具有一定优势；怀牛膝通过改变OA病变软骨组织中NOS、SOD活性,保护软骨组织延缓病情发展,并且这一作用存在量效关系；怀牛膝能通过抑制MMPs表达以及增加TIMP-1表达来控制OA病情；有效浓度的怀牛膝能通过提高OA软骨组织中的IGF-1和II型胶原蛋白的表达以延缓病情发展。
Objective
Observed the pathophysiological changes of the knee joint's articular cartilage of osteoarthritis model of rabbit, to further explore the nosogenesis of osteoarthritis and analysis the Achyranthes bidentata mechanism of action of OA rabbit knee cartilage, to provide some basis for experimental research and clinical application in field of Chinese medicine prevention and treatment of osteoarthritis.
Methods
New Zealand white rabbits were randomly divided into normal group, model group, treatment groups (Achyranthes bidentata) and the control group (Celebrex). The treatment groups were divided into Achyranthes bidentata high dose group, Achyranthes bidentata middle dose group and Achyranthes bidentata low dose group. Reference to the Hulth's Modeling method to make the experimental rabbit knee OA model. Harvested the rabbits with macth dose Achyranthes bidentata after modeling one week, six weeks of continuous treatment, detected the changes of morphology and pathophysiology of lesions cartilage tissue, specifically divided into four parts:
1Use the Chemical Preparation of cartilage tissue slices, to observed lesions of cartilage tissue morphological changes observed in the light microscope and electron microscope.
2Extracted the synovial fluid of knee joint, to detect the content of NOS and SOD by the chemical colorimetric assay.
3Use the Western blot method to detect the expression of MMP-3, MMP-13and TIMP-1in synovial tissue. Compared the deference of each group by image analysis system.
4The use of immunohistochemical techniques were used to detect the expression of cartilage tissue's IGF-1and type Ⅱ collagen. Compared the deference of each group by image analysis system.
Results
1Histological changes:the normal group of the articular cartilage surface was smooth, evenly distributed chondrocytes; cartilage tissue surface of the model group was significantly thinner, showing that the cells clustered chondrocytes derangement; Achyranthes bidentata high dose group, Achyranthes bidentata medium dose group and control group's cartilage tissue damage were reduced significantly, a few regions visible cartilage cells arranged in irregular; Achyranthes bidentata low-dose group had little difference with the model group. Cartilage tissue score:the model group's score increased than the normal group (P<0.01). The score of Achyranthes bidentata high dose group, medium dose group and control group were significantly lower than the model group (P<0.01). There were no significant difference between the medium dose group and high dose group (P>0.05), but the two groups both had differences compared with the control group (P<0.01). No significant differences between Achyranthes bidentata low dose group and the model group (P>0.05). Electron microscope obse rvation:the cartilage cells of the normal group were normal; the model group's cartilage cells had irregular shape. There were condensation phenomenon in cartilage tissue; Achyranthes bidentata high dose group and medium dose group,the chondrocyte had Mildly abnormal. Part of the chondrocyte had some vacuoles. The degree of cell damage was better than the control group and Achyranthes bidentata low dose group.
2NOS values in the synovial fluid of model group had significantly increased than in normal group (P<0.01). Achyranthes bidentata high dose group, Achyranthes bidentata medium dose group and control group were significantly lower than the model group (P<0.01). NOS values of the control group and Achyranthes bidentata high dose group were lower than NOS values of Achyranthes bidentata medium dose group (P<0.01). Achyranthes bidentata low dose group had no difference with model group (P>0.05). SOD values in the synovial fluid of model group had significantly decreased than in normal group(P<0.01). Achyranthes bidentata high dose group SOD levels was higher than the medium dose group, and the two groups had significantly increased than the model group (P<0.01).There were no difference between Achyranthes bidentata low dose group、 control group and model group (P>0.05)
3The expression of MMP-3、MMP-13in synovial tissue had no difference between Achyranthes bidentata high dose group、 Achyranthes bidentata medium dose group and control group (P>0.05). The three groups were lower than model group (P<0.01). The expression of TIMP-1in synovial tissue of Achyranthes bidentata high dose group and Achyranthes bidentata medium dose group and control group were higher than model group (P<0.01). The expression of TIMP-1in synovial tissue of Achyranthes bidentata high dose group and Achyranthes bidentata medium dose group were higher than the control group (P<0.05). The expression of MMP-3、MMP-13and TIMP-1in synovial tissue had no difference between Achyranthes bidentata low dose group and model group (P>0.05)
4IGF-1expression of Achyranthes bidentata high dose group was higher than the middle dose group (P<0.01), and the two groups were significantly higher than control group、the Achyranthes bidentata low dose group and model group (P<0.01). Expression of collagen Ⅱ, Achyranthes high-dose group and medium dose group control group and model group were higher than model group(P<0.01). Achyranthes high-dose group and medium dose group were higher than control group (P<0.05). Achyranthes low-dose group had no difference with model group (P>0.05)
Conclusions
A certain dose of Achyranthes bidentata can delay the degener ation of cartilage tissue in the OA model; Achyranthes bidentata probably by altering the OA lesion cartilage tissue's NOS and SOD activity, to protect the cartilage tissue and delay the progression of the disease; Achyranthes bidentata can inhibit the expression of MMPs and increase TIMP-1expression to control the OA disease development. The effective concentration of Achyranthes bidentata can through the way of increase expression of IGF-1and type Ⅱ collagen protein in OA cartilage tissue to delay the progression of the disease.
观察骨关节炎模型兔膝关节软骨组织的病理生理变化,探讨怀牛膝对骨关节炎模型兔膝关节软骨组织的作用机制,为中医药防治骨性关节炎的实验研究与临床应用提供一些依据。
方法
新西兰大白兔随机分为正常组、模型组、治疗组(怀牛膝)、对照组(西乐葆),其中治疗组分为怀牛膝高剂量、中剂量和低剂量三组。参照Hulth造模法制作实验性兔骨关节炎模型。造模一周后开始给药,连续治疗6周后取材,分别检测病灶软骨组织形态及病理生理学相关因子的变化,具体分四个部分：
1采用组织化学法制备软骨组织标本及切片,在光镜和电镜下观察病灶软骨组织形态学变化。
2在切开病灶膝关节之前抽取关节液,采用化学比色法检测关节液中NOS、SOD的含量。
3运用免疫印迹法分别检测滑膜组织中MMP-3、MMP-13、TIMP-1表达,通过图像分析系统比较各组之间差异。
4运用免疫组织化学技术分别检测软骨组织IGF-1和II型胶原,通过图像分析系统比较各组之间差异。
结果
1组织形态学变化：正常组关节软骨组织表层光滑、平整,软骨细胞分布均匀；模型组软骨组织表层明显变薄甚至消失,可见细胞簇集,软骨细胞排列紊乱；治疗组中怀牛膝高、中剂量组和对照组软骨组织破坏程度明显减轻,少数区域可见软骨细胞排列不规则；怀牛膝低剂量组和模型组差别不大。各组软骨组织评分中模型组较正常组评分明显升高(P<0.01)；怀牛膝高、中剂量组和对照组较模型组显著降低(P<0.01)；怀牛膝高、中剂量组组间比较无明显差异,但分别较对照组存在差异；怀牛膝低剂量组与模型组之间差异不明显(P>0.05)。电镜下观察正常组软骨细胞基本正常；模型组软骨细胞外形不规则,软骨细胞有固缩现象；怀牛膝高、中剂量组软骨细胞轻度异常,部分出现空泡,胞浆内细胞器增多；且细胞损伤程度好于对照组和怀牛膝低剂量组。
2关节液中NOS含量模型组较正常组明显升高(P<0.01)；怀牛膝高、中剂量和对照组较模型组均明显降低(P<0.01),且对照组和怀牛膝高剂量组NOS含量低于中剂量组；怀牛膝低剂量组与模型组间无明显差异(P>0.05)。关节液中SOD含量模型组较正常组明显降低(P<0.01)；怀牛膝高剂量组SOD含量高于中剂量,且两组均比模型组明显升高(P<0.01),低剂量组和对照组与模型组比较差异不明显(P>0.05)。
3病灶侧滑膜组织中MMP-3和MMP-13在治疗组中怀牛膝高、中剂量组和对照组之间差异不明显(P>0.05),三组与模型组之间比较差异明显(P<0.01);TIMP-1数值在怀牛膝高、中剂量组和对照组与模型组比较均差异显著(P<0.01)；而怀牛膝高、中剂量组较对照组也存在差异(P<0.05)；怀牛膝低剂量组MMP-3、MMP-13和TIMP-1数值与模型组间无明显差异(P>0.05)。
4病变组织中IGF-1表达怀牛膝高剂量组高于中剂量组(P<0.01),且两组均明显高于对照组、怀牛膝低剂量组和模型组(P<0.01)。病变组织中II胶原的表达,怀牛膝高、中剂量组和对照组与模型组比较差异明显(P<0.01),且高、中剂量组好于对照组(P<0.05)；低剂量组与模型组比较无差异(P>0.05)。
结论
怀牛膝有延缓OA模型中软骨组织退变的作用,且相对与西乐葆具有一定优势；怀牛膝通过改变OA病变软骨组织中NOS、SOD活性,保护软骨组织延缓病情发展,并且这一作用存在量效关系；怀牛膝能通过抑制MMPs表达以及增加TIMP-1表达来控制OA病情；有效浓度的怀牛膝能通过提高OA软骨组织中的IGF-1和II型胶原蛋白的表达以延缓病情发展。
Objective
Observed the pathophysiological changes of the knee joint's articular cartilage of osteoarthritis model of rabbit, to further explore the nosogenesis of osteoarthritis and analysis the Achyranthes bidentata mechanism of action of OA rabbit knee cartilage, to provide some basis for experimental research and clinical application in field of Chinese medicine prevention and treatment of osteoarthritis.
Methods
New Zealand white rabbits were randomly divided into normal group, model group, treatment groups (Achyranthes bidentata) and the control group (Celebrex). The treatment groups were divided into Achyranthes bidentata high dose group, Achyranthes bidentata middle dose group and Achyranthes bidentata low dose group. Reference to the Hulth's Modeling method to make the experimental rabbit knee OA model. Harvested the rabbits with macth dose Achyranthes bidentata after modeling one week, six weeks of continuous treatment, detected the changes of morphology and pathophysiology of lesions cartilage tissue, specifically divided into four parts:
1Use the Chemical Preparation of cartilage tissue slices, to observed lesions of cartilage tissue morphological changes observed in the light microscope and electron microscope.
2Extracted the synovial fluid of knee joint, to detect the content of NOS and SOD by the chemical colorimetric assay.
3Use the Western blot method to detect the expression of MMP-3, MMP-13and TIMP-1in synovial tissue. Compared the deference of each group by image analysis system.
4The use of immunohistochemical techniques were used to detect the expression of cartilage tissue's IGF-1and type Ⅱ collagen. Compared the deference of each group by image analysis system.
Results
1Histological changes:the normal group of the articular cartilage surface was smooth, evenly distributed chondrocytes; cartilage tissue surface of the model group was significantly thinner, showing that the cells clustered chondrocytes derangement; Achyranthes bidentata high dose group, Achyranthes bidentata medium dose group and control group's cartilage tissue damage were reduced significantly, a few regions visible cartilage cells arranged in irregular; Achyranthes bidentata low-dose group had little difference with the model group. Cartilage tissue score:the model group's score increased than the normal group (P<0.01). The score of Achyranthes bidentata high dose group, medium dose group and control group were significantly lower than the model group (P<0.01). There were no significant difference between the medium dose group and high dose group (P>0.05), but the two groups both had differences compared with the control group (P<0.01). No significant differences between Achyranthes bidentata low dose group and the model group (P>0.05). Electron microscope obse rvation:the cartilage cells of the normal group were normal; the model group's cartilage cells had irregular shape. There were condensation phenomenon in cartilage tissue; Achyranthes bidentata high dose group and medium dose group,the chondrocyte had Mildly abnormal. Part of the chondrocyte had some vacuoles. The degree of cell damage was better than the control group and Achyranthes bidentata low dose group.
2NOS values in the synovial fluid of model group had significantly increased than in normal group (P<0.01). Achyranthes bidentata high dose group, Achyranthes bidentata medium dose group and control group were significantly lower than the model group (P<0.01). NOS values of the control group and Achyranthes bidentata high dose group were lower than NOS values of Achyranthes bidentata medium dose group (P<0.01). Achyranthes bidentata low dose group had no difference with model group (P>0.05). SOD values in the synovial fluid of model group had significantly decreased than in normal group(P<0.01). Achyranthes bidentata high dose group SOD levels was higher than the medium dose group, and the two groups had significantly increased than the model group (P<0.01).There were no difference between Achyranthes bidentata low dose group、 control group and model group (P>0.05)
3The expression of MMP-3、MMP-13in synovial tissue had no difference between Achyranthes bidentata high dose group、 Achyranthes bidentata medium dose group and control group (P>0.05). The three groups were lower than model group (P<0.01). The expression of TIMP-1in synovial tissue of Achyranthes bidentata high dose group and Achyranthes bidentata medium dose group and control group were higher than model group (P<0.01). The expression of TIMP-1in synovial tissue of Achyranthes bidentata high dose group and Achyranthes bidentata medium dose group were higher than the control group (P<0.05). The expression of MMP-3、MMP-13and TIMP-1in synovial tissue had no difference between Achyranthes bidentata low dose group and model group (P>0.05)
4IGF-1expression of Achyranthes bidentata high dose group was higher than the middle dose group (P<0.01), and the two groups were significantly higher than control group、the Achyranthes bidentata low dose group and model group (P<0.01). Expression of collagen Ⅱ, Achyranthes high-dose group and medium dose group control group and model group were higher than model group(P<0.01). Achyranthes high-dose group and medium dose group were higher than control group (P<0.05). Achyranthes low-dose group had no difference with model group (P>0.05)
Conclusions
A certain dose of Achyranthes bidentata can delay the degener ation of cartilage tissue in the OA model; Achyranthes bidentata probably by altering the OA lesion cartilage tissue's NOS and SOD activity, to protect the cartilage tissue and delay the progression of the disease; Achyranthes bidentata can inhibit the expression of MMPs and increase TIMP-1expression to control the OA disease development. The effective concentration of Achyranthes bidentata can through the way of increase expression of IGF-1and type Ⅱ collagen protein in OA cartilage tissue to delay the progression of the disease.
引文
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