[1]王金杰,俞倩丽,范魏魏,等.舒尼替尼干预大鼠膝骨关节炎的实验研究[J].中医正骨,2018,30(01):1-5.
　WANG Jinjie,YU Qianli,FAN Weiwei,et al.An experimental study of sunitinib for prevention of knee osteoarthritis in rats[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2018,30(01):1-5.
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舒尼替尼干预大鼠膝骨关节炎的实验研究()
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《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第30卷
期数:
2018年01期
页码:
1-5
栏目:
基础研究
出版日期:
2018-01-20

文章信息/Info

Title:
An experimental study of sunitinib for prevention of knee osteoarthritis in rats
作者:
王金杰1; 俞倩丽1; 范魏魏1; 庄汝杰2
1.浙江中医药大学,浙江 杭州 310053; 2.浙江省中医院,浙江 杭州 310006
Author(s):
WANG Jinjie1; YU Qianli1; FAN Weiwei1; ZHUANG Rujie2
1.Zhejiang Chinese Medical University,Hangzhou 310053,Zhejiang,China 2.Zhejiang Provincial Hospital of Traditional Chinese Medicine,Hangzhou 310006,Zhejiang,China
关键词:
骨关节炎; 膝;  血管内皮生长因子类;  基质金属蛋白酶13;  舒尼替尼;  动物实验
Keywords:
Keywords osteoarthritis; knee;  vascular endothelial growth factors;  matrix metalloproteinase 13;  sunitinib;  animal experimentation
摘要:
目的:探讨舒尼替尼对大鼠膝骨关节炎(knee osteoarthritis,KOA)的影响。方法:选取32只雄性SD大鼠,随机分为空白组、模型组、4周治疗组及8周治疗组,每组8只。除空白组外,其余3组大鼠均采用木瓜蛋白酶进行KOA造模。造模完成后,空白组大鼠正常喂养; 4周治疗组和8周治疗组大鼠按照1 mg·kg-1以舒尼替尼灌胃,每天1次,2组分别持续干预4周和8周; 模型组大鼠每天以同等体积生理盐水灌胃。药物干预结束后处死各组大鼠,分别进行膝关节MRI检查、关节液血管内皮生长因子(vascular endothelial growth factor,VEGF)和基质金属蛋白酶(matrix metalloproteinase,MMP)-13水平测定、膝关节组织病理学观察。结果:①膝关节MRI检查结果。大鼠膝关节矢状位MRI显示,空白组大鼠膝关节结构完整,关节表面有完整的软骨,表面光滑,软骨与骨组织连接紧密,软骨下无炎症及囊性病变,软骨下骨无磨损、无骨赘; 模型组大鼠膝关节结构明显破坏,表面软骨明显磨损,特别是胫骨平台有明显软骨及软骨下骨破损,软骨下有囊性病变; 4周治疗组大鼠膝关节结构基本完整,软骨略粗糙,但胫骨平台下仍见软骨下炎症及软骨下骨破损,软骨下存在囊性病变; 8周治疗组大鼠膝关节结构完整,软骨完整光滑,软骨下骨无明显破损,软骨下无明显囊性病变,但软骨下仍有一定程度的炎症。②膝关节液VEGF、MMP-13水平测定结果。4组大鼠关节液VEGF水平比较,差异有统计学意义[(152.26±31.17)pg·mL-1,(237.95±69.10)pg·mL-1,(168.43±47.47)pg·mL-1,(136.75±27.48)pg·mL-1,F=14.575,P=0.000]。模型组关节液VEGF水平高于空白组、4周治疗组和8周治疗组(P=0.000,P=0.000,P=0.000); 空白组与4周治疗组、8周治疗组比较,差异均无统计学意义(P=0.332,P=0.181); 4周治疗组与8周治疗组比较,差异无统计学意义(P=0.060)。4组大鼠关节液MMP-13水平比较,差异有统计学意义[(60.85±13.70)pg·mL-1,(94.98±37.63)pg·mL-1,(75.43±20.23)pg·mL-1,(68.54±19.82)pg·mL-1,F=5.686,P=0.002]。模型组关节液MMP-13水平高于空白组、4周治疗组和8周治疗组(P=0.028,P=0.003,P=0.000); 空白组与4周治疗组、8周治疗组比较,差异均无统计学意义(P=0.098,P=0.242); 4周治疗组与8周治疗组比较,差异无统计学意义(P=0.431)。③膝关节组织病理学观察结果。空白组大鼠膝关节整体结构完整,软骨面光滑,无坏死、溃疡,骨小梁结构、形态完整; 模型组大鼠膝关节有典型的软骨受损表现,软骨面不光滑,部分软骨脱失,软骨细胞排列紊乱,骨小梁不完整; 4周治疗组大鼠膝关节面较模型组略光滑,软骨细胞排列尚整齐、分布均匀,骨小梁的结构、形态较模型组完整,但仍有部分碎裂; 8周治疗组大鼠膝关节软骨光滑,软骨细胞分布均匀、排列整齐,各层次清晰,无明显细胞簇集现象,潮线完整,骨小梁结构基本完整。结论:舒尼替尼能通过抑制KOA大鼠膝关节VEGF的表达,抑制MMP-13的表达,从而延缓膝关节退变,其效果与作用时间有关。
Abstract:
ABSTRACT Objective:To explore the effect of sunitinib on knee osteoarthritis(KOA)in rats.Methods:Thirty-two male SD rats were selected and were randomly divided into blank group,model group,4-week treatment group and 8-week treatment group,8 cases in each group.The KOA rat models were created in model group,4-week treatment group and 8-week treatment group by using papain,while the rats in blank group were not given any intervention.After the modeling,the rats in blank group were fed normally,and the rats in 4-week treatment group and 8-week treatment group were intragastric administrated with sunitinib(1 mg/kg),once a day for consecutive 4 and 8 weeks respectively; while the rats in model group were intragastric administrated with the same dose of normal saline everyday.After the end of drug intervention,the rats in each group were executed.MRI examination and histopathological observation on knee joint and determination of knee joint fluid level of vascular endothelial growth factor(VEGF)and matrix metalloproteinase(MMP)-13 were performed on rats in each group.Results:The results of sagittal MRI examination of knee joint showed that in blank group(1)the structure of knee-joint was complete;(2)the articular surface was smooth and the articular cartilage was intact;(3)the cartilage tissue was closely connected with bone tissue;(4)no inflammation and cystis degeneration were found under cartilage;(5)no abrasion and osteophyte were found in subchondral bone.The sagittal MRI images also showed that in model group(1)the structure of knee-joint was obviously damaged;(2)the superne cartilage was obviously worn;(3)obvious damages of cartilage and subchondral bone and obvious subchondral cystis degeneration were found under the tibial plateau.In 4-week treatment group,the structure of knee-joint was basically intact and the cartilage was roughish,while subchondral inflammation,bone damages and cystis degeneration were found under the tibial plateau.In 8-week treatment group,the structure of knee-joint was intact and the cartilage was complete and smooth,and no obvious subchondral bone damages and subchondral cystis degeneration were found,while some subchondral inflammation was found.There was statistical difference in the level of VEGF in knee joint fluid between the 4 groups(152.26+/-31.17,237.95+/-69.10,168.43+/-47.47,136.75+/-27.48 pg/mL,F=14.575,P=0.000).The level of VEGF in knee joint fluid was higher in model group compared to blank group,4-week treatment group and 8-week treatment group(P=0.000,P=0.000,P=0.000); and there was no statistical difference in the level of VEGF between blank group and 4-week treatment group and between blank group and 8-week treatment group(P=0.332,P=0.181); and there was no statistical difference in the level of VEGF between 4-week treatment group and 8-week treatment group(P=0.060).There was statistical difference in the level of MMP-13 in knee joint fluid between the 4 groups(60.85+/-13.70,94.98+/-37.63,75.43+/-20.23,68.54+/-19.82 pg/mL,F=5.686,P=0.002).The level of MMP-13 in knee joint fluid was higher in model group compared to blank group,4-week treatment group and 8-week treatment group(P=0.028,P=0.003,P=0.000); and there was no statistical difference in the level of MMP-13 between blank group and 4-week treatment group and between blank group and 8-week treatment group(P=0.098,P=0.242); and there was no statistical difference in the level of MMP-13 between 4-week treatment group and 8-week treatment group(P=0.431).The results of histopathological observation on knee joints of rats in blank group showed that(1)the integral structure of the knee joint was complete;(2)the surface of cartilage was smooth without necrosis and ulcer;(3)the structure and morphology of the trabecular bone were complete.The results of histopathological observation on knee joints of rats in model group showed that(1)the knee joint was characterized by typical cartilaginous damage;(2)the surface of cartilage was unsmooth and some of the cartilages were lost;(3)the chondrocytes were disorganized;(4)the trabecular bone was incomplete.In 4-week treatment group,the knee joint surface was slightly smoother compared to model group,and the chondrocytes were regularly arranged and uniformly distributed,and the structure and morphology of the trabecular bone were more complete compared to model group,while some fragments of trabecular bone were still found.In 8-week treatment group,the knee articular cartilage was smooth and the chondrocytes uniformly distributed and regularly arranged with clear layers; no chondrocytes clustered together,and the tidal line was complete and the structure of trabecular bone was basically complete.Conclusion:Sunitinib can inhibit the expression of MMP-13 through inhibiting the expression of VEGF in knee joints of KOA rat models,which may be the mechanisms of action for delaying knee joint degeneration,and its effect is related to the action time.

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备注/Memo

备注/Memo:
基金项目:2014年浙江省重大科技专项计划项目(2014C03038); 2016年浙江中医药科技计划项目(2016ZA085) 通讯作者:庄汝杰 E-mail:rujiezhuang@163.com
更新日期/Last Update: 2018-06-02