[1]向文远,易林,张文豪,等.补肾痹通方联合骨髓间充质干细胞干预膝骨关节炎的效果及其作用机制研究[J].中医正骨,2025,37(09):16-35.
　XIANG Wenyuan,YI Lin,ZHANG Wenhao,et al.Efficacy and mechanism of Bushen Bitong Fang(补肾痹通方)combined with bone marrow mesenchymal stem cells against knee osteoarthritis[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2025,37(09):16-35.
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补肾痹通方联合骨髓间充质干细胞干预膝骨关节炎的效果及其作用机制研究()

《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第37卷
期数:
2025年09期
页码:
16-35
栏目:
膝骨关节炎
出版日期:
2025-09-20

文章信息/Info

Title:
Efficacy and mechanism of Bushen Bitong Fang(补肾痹通方)combined with bone marrow mesenchymal stem cells against knee osteoarthritis
作者:
向文远; 易林; 张文豪; 邓迎杰; 方锐
(新疆医科大学第四临床医学院,新疆 乌鲁木齐 830000)
Author(s):
XIANG Wenyuan; YI Lin; ZHANG Wenhao; DENG Yingjie; FANG Rui
The Fourth Clinical Medical College of Xinjiang Medical University,Urumqi 830000,Xinjiang,China
关键词:
骨关节炎; 膝;  补肾痹通方;  间质干细胞;  骨髓;  软骨细胞;  细胞凋亡;  类Toll受体;  髓系分化初级反应蛋白质88;  NF-κB;  动物实验
Keywords:
osteoarthritis; knee;  Bushen Bitong Fang;  mesenchymal stem cells;  bone marrow;  chondrocytes;  apoptosis;  Toll-like receptors;  myeloid differentiation primary response protein 88;  NF-kappa B;  animal experimentation
摘要:
目的:探讨补肾痹通方联合骨髓间充质干细胞(bone marrow mesenchymal stem cell,BMMSC)干预膝骨关节炎(knee osteoarthritis,KOA)的效果及其作用机制。方法:①细胞实验。将软骨细胞接种于96孔Transwell小室的下室中,分为空白对照组、模型组、补肾痹通方含药血清组、BMMSC组和联合干预组,除空白对照组外,其余4组均加入终浓度为10 ng·mL-1的白细胞介素-1β,诱导KOA细胞模型。诱导结束后,在Transwell小室的上室中,补肾痹通方含药血清组加入含15%补肾痹通方含药血清的培养基,BMMSC组加入等量的BMMSC悬液,联合干预组加入含15%补肾痹通方含药血清的培养基及等量的BMMSC悬液,空白对照组和模型组加入等量的空白培养基。继续培养24 h后,取出Transwell小室的上室,统计各组软骨细胞数量,计算各组软骨细胞相对迁移率。将软骨细胞接种于96孔细胞培养板中,采用相同的分组、造模与干预方式,继续培养24 h后,采用流式细胞术检测各组软骨细胞的凋亡率,采用Western Blot法检测各组软骨细胞B淋巴细胞瘤-2相关X蛋白(B-cell lymphoma-2 associated X protein,BAX)、B淋巴细胞瘤(B-cell lymphoma,Bcl)-2、活化的半胱氨酸天冬氨酸蛋白酶-3(cleaved-cysteine aspartic acid specific protease-3,cleaved-Caspase-3)等细胞凋亡相关基因的蛋白表达量。②动物实验。将40只大鼠随机分为假手术组、模型组、BMMSC组和联合干预组,每组10只。模型组、BMMSC组、联合干预组采用改良Hulth法建立大鼠右侧KOA模型,假手术组大鼠切开右侧膝关节皮肤及皮下组织、暴露膝关节腔后缝合。造模4周后,向BMMSC组、联合干预组大鼠右侧膝关节腔内注射100 μL BMMSC悬液(细胞数量约为200个·μL-1),向假手术组、模型组大鼠右侧膝关节腔内注射100 μL生理盐水,各组大鼠每周注射1次,连续注射4周。联合干预组按照生药16.35 g·kg-1·d-1给予补肾痹通方药液灌胃,分2次早晚灌服,连续灌胃4周。干预结束后,每组随机选取4只大鼠,分离右侧膝关节,观察大鼠膝关节软骨组织病理变化; 其余6只大鼠,分离大鼠右侧膝关节软骨组织,检测大鼠膝关节软骨组织中Toll样受体(Toll-like receptor,TLR)4、髓系分化初级反应蛋白质88(myeloid differentiation primary response protein 88,MyD88)、核因子κB(nuclear factor-κB,NF-κB)p65的mRNA表达量以及TLR4、MyD88、NF-κB p65、磷酸化核因子κB(phosphorylated nuclear factor-κB,p-NF-κB)p65的蛋白表达量。结果:①补肾痹通方含药血清联合BMMSC对软骨细胞迁移活性影响的分析结果。模型组软骨细胞相对迁移率低于空白对照组(P=0.000),补肾痹通方含药血清组、BMMSC组、联合干预组软骨细胞相对迁移率均高于模型组(P=0.000,P=0.010,P=0.016),联合干预组软骨细胞相对迁移率高于补肾痹通方含药血清组和BMMSC组(P=0.000,P=0.012)。②补肾痹通方含药血清联合BMMSC对软骨细胞凋亡影响的分析结果。模型组软骨细胞凋亡率高于空白对照组(P=0.000),补肾痹通方含药血清组、BMMSC组、联合干预组软骨细胞凋亡率均低于模型组(P=0.000,P=0.010,P=0.016),联合干预组软骨细胞凋亡率低于补肾痹通方含药血清组和BMMSC组(P=0.000,P=0.000)。模型组软骨细胞BAX、cleaved-Caspase-3的蛋白相对表达量及BAX与Bcl-2蛋白相对表达量的比值均高于空白对照组(P=0.000,P=0.000,P=0.000),Bcl-2蛋白相对表达量低于空白对照组(P=0.000); 补肾痹通方含药血清组、BMMSC组、联合干预组软骨细胞BAX、cleaved-Caspase-3的蛋白相对表达量及BAX与Bcl-2蛋白相对表达量的比值均低于模型组(BAX:P=0.000,P=0.010,P=0.016; cleaved-Caspase-3:P=0.000,P=0.010,P=0.000; BAX与Bcl-2的比值:P=0.000,P=0.010,P=0.000),Bcl-2蛋白相对表达量高于模型组(P=0.000,P=0.000,P=0.001); 联合干预组软骨细胞BAX、cleaved-Caspase-3的蛋白相对表达量及BAX与Bcl-2蛋白相对表达量的比值均低于补肾痹通方含药血清组和BMMSC组(P=0.000,P=0.020; P=0.002,P=0.022; P=0.000,P=0.000),Bcl-2蛋白相对表达量高于补肾痹通方含药血清组和BMMSC组(P=0.010,P=0.049)。③大鼠膝关节软骨组织病理学观察结果。模型组大鼠膝关节软骨表面粗糙,有裂隙和褶皱,潮线不完整,软骨下骨不规则增厚,软骨细胞大小不一、分布不均匀、排列不规则; BMMSC组和联合干预组大鼠膝关节软骨的退变情况较模型组改善,且联合干预组较BMMSC组改善更明显。④大鼠膝关节软骨组织中TLR4-MyD88-NF-κB信号通路相关基因的mRNA和蛋白表达量检测结果。模型组大鼠膝关节软骨组织中TLR4、MyD88、NF-κB p65的mRNA相对表达量均高于假手术组(P=0.000,P=0.000,P=0.000),BMMSC组和联合干预组大鼠膝关节软骨组织中TLR4、MyD88、NF-κB p65的mRNA相对表达量均低于模型组(P=0.000,P=0.011,P=0.038; P=0.000,P=0.000,P=0.001),联合干预组大鼠膝关节软骨组织中TLR4、MyD88、NF-κB p65的mRNA相对表达量均低于BMMSC组(P=0.001,P=0.039,P=0.045)。4组大鼠膝关节软骨组织中NF-κB p65的蛋白相对表达量的组间差异无统计学意义(F=1.797,P=0.226)。模型组大鼠膝关节软骨组织中TLR4、MyD88、p-NF-κB p65的蛋白相对表达量均高于假手术组(P=0.000,P=0.000,P=0.000),BMMSC组和联合干预组大鼠膝关节软骨组织中TLR4、MyD88、p-NF-κB p65的蛋白相对表达量均低于模型组(P=0.022,P=0.025,P=0.026; P=0.000,P=0.000,P=0.000),联合干预组大鼠膝关节软骨组织中TLR4、MyD88、p-NF-κB p65的蛋白相对表达量均低于BMMSC组(P=0.011,P=0.003,P=0.025)。结论:补肾痹通方联合BMMSC干预KOA,能够促进软骨组织的修复,其作用机制与抑制TLR4-MyD88-NF-κB信号通路的激活及软骨细胞凋亡有关。
Abstract:
Objective:To investigate the therapeutic efficacy of Bushen Bitong Fang(补肾痹通方,BSBTF)combined with bone marrow mesenchymal stem cells(BMMSCs)against knee osteoarthritis(KOA),and to explore its underlying mechanism.Methods:①Cell experiment.The chondrocytes were seeded into the lower chamber of 96-well Transwell chamber and allocated into blank control group,model group,BSBTF medicated serum group,BMMSC group,and combined intervention group.All chondrocytes but the ones in blank control group were intervened with interleukin-1β(IL-1β)at a final concentration of 10 ng/mL for 24 hours to induce in vitro KOA cell models.Following the model induction,in the upper chamber of the Transwell chamber,the chondrocytes in the BSBTF medicated serum group were further intervened with medium containing 15% BSBTF medicated serum,the ones in BMMSC group with an equal volume of BMMSC suspension,the ones in combined intervention group with both medium containing 15% BSBTF medicated serum and an equal volume of BMMSC suspension,while the ones in blank control group and model group with an equal volume of blank medium for another 24 hours.After the end of the intervention,the upper chamber of the Transwell chamber was removed for quantifying the chondrocytes and calculating the relative migration rate of chondrocytes in each group.In a parallel experiment,the chondrocytes were seeded into 96-well cell culture plates and subjected to the identical grouping,modeling,and intervention protocols.After 24-hour incubation,the apoptosis rate of chondrocytes in each group was determined using flow cytometry,and the protein expression levels of key apoptosis-related genes,including B-cell lymphoma-2 associated X protein(BAX),B-cell lymphoma(Bcl)-2,and cleaved-cysteine aspartic acid specific protease-3(cleaved-Caspase-3),were detected in each group by Western Blot.②Animal experiment.Forty rats were randomly assigned into sham-operated group,model group,BMMSC group,and combined intervention group,with 10 rats in each group.All rats but the ones in sham-operated group were subjected to surgeries on the right knee joints by using modified Hulth method to build KOA models,while the ones in sham-operated group were merely incised the skin and subcutaneous tissues at the corresponding site and then sutured after exposing the knee joint cavity.Four weeks after the modeling,the rats in BMMSC group and combined intervention group were intervened by right knee intra-articular injection of 100 μL BMMSC suspension(approximately 200 cells/μL),while the rest 2 groups by intra-articular injection of 100 μL sterile saline at the corresponding sites,once a week for consecutive 4 weeks.Additionally,the rats in combined intervention group were further intervened by intragastric administration with BSBTF decoction at a crude dose of 16.35 g/kg/day,once in the morning and evening,respectively,for consecutive 4 weeks.After the end of intervention,all rats were sacrificed.Four rats were randomly selected from each group,and their right knee joints were dissected for observing the histopathological changes of the knee articular cartilage.In addition,the right knee articular cartilage tissues were harvested from the remaining 6 rats in each group for detecting the mRNA expression levels of Toll-like receptor(TLR)4,myeloid differentiation primary response protein 88(MyD88),and nuclear factor-κB(NF-κB)p65,as well as the protein expression levels of TLR4,MyD88,NF-κB p65,and phosphorylated nuclear factor-κB(p-NF-κB)p65.Results:①Effects of BSBTF medicated serum combined with BMMSCs on the migration activity of chondrocytes.The relative migration rate of chondrocytes decreased in model group compared to blank control group(P=0.000),while it increased in BSBTF medicated serum group,BMMSC group,and combined intervention group compared to model group(P=0.000,P=0.010,P=0.016),with the greater value in combined intervention group compared to BSBTF medicated serum group and BMMSC group alone(P=0.000,P=0.012).②Effects of BSBTF medicated serum combined with BMMSCs on the apoptosis of chondrocytes.The chondrocyte apoptosis rate was higher in model group compared to blank control group(P=0.000),while,was lower in BSBTF medicated serum group,BMMSC group,and combined intervention group compared to model group(P=0.000,P=0.010,P=0.016),with the lower value in combined intervention group compared to BSBTF medicated serum group and BMMSC group alone(P=0.000,P=0.000).The relative protein expression levels of BAX and cleaved-Caspase-3,as well as the ratio of BAX to Bcl-2,were all higher,while that of Bcl-2 was lower in model group compared to blank control group(P=0.000,P=0.000,P=0.000,P=0.000); furthermore,the relative protein expression levels of BAX and cleaved-Caspase-3,as well as Bax/Bcl-2 ratio,were all lower,while that of Bcl-2 was higher in BSBTF medicated serum group,BMMSC group,and combined intervention group compared to model group(BAX:P=0.000,P=0.010,P=0.016; cleaved-Caspase-3:P=0.000,P=0.010,P=0.000; Bax/Bcl-2 ratio:P=0.000,P=0.010,P=0.000; Bcl-2:P=0.000,P=0.000,P=0.001),with the combined intervention group showing the lowest values in the relative protein expression levels of BAX and cleaved-Caspase-3,as well as Bax/Bcl-2 ratio,and the highest value in that of Bcl-2 among the 3 treatment groups(P=0.000,P=0.020; P=0.002,P=0.022; P=0.000,P=0.000; P=0.010,P=0.049).③Histopathological findings in rat knee articular cartilage.The marked changes,manifesting as a rough articular cartilage surface with the presence of fissures and folds,an incomplete tide line,irregularly thickened subchondral bone,accompanied by unevenly distributed,and irregularly arranged chondrocytes showing heterogeneous in size,were observed in the knee articular cartilage of rats in model group,while,compared with that of model group,the knee articular cartilage degeneration was attenuated in both BMMSC group and combined intervention group,with marked amelioration demonstrated in combined intervention group.④The mRNA and protein expression of TLR4-MyD88-NF-κB signaling pathway-related genes in rat knee articular cartilage tissues.The relative mRNA expression levels of TLR4,MyD88,and NF-κB p65 in rat knee articular cartilage tissues were higher in model group compared to sham-operated group(P=0.000,P=0.000,P=0.000),while,were lower in both treatment groups(BMMSC group and combined intervention group)compared to model group(P=0.000,P=0.011,P=0.038; P=0.000,P=0.000,P=0.001),with the lower value observed in combined intervention group compared to BMMSC group(P=0.001,P=0.039,P=0.045).However,the relative protein expression level of NF-κB p65 in the knee articular cartilage tissues showed no significant difference among the 4 groups(F=1.797,P=0.226).In addition,the relative protein expression levels of TLR4,MyD88,and p-NF-κB p65 in the knee articular cartilage tissues were higher in model group compared to sham-operated group(P=0.000,P=0.000,P=0.000),while,were lower in BMMSC group and combined intervention group compared to model group(P=0.022,P=0.025,P=0.026; P=0.000,P=0.000,P=0.000),with the lower value observed in combined intervention group compared to BMMSC group(P=0.011,P=0.003,P=0.025).Conclusion:BSBTF combined with BMMSCs can promote the repair of cartilage tissues in KOA.It may work by inhibiting the activation of TLR4-MyD88-NF-κB signaling pathway and suppressing the apoptosis of chondrocytes.

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备注/Memo

备注/Memo:
基金项目:“天山英才”培养计划科技创新领军人才项目(2022TSYCLJ0007); “天山英才”培养计划青年托举人才项目(2023TSYCQNTJ0050)
通讯作者:方锐 E-mail:xjfrdoctor@163.com
更新日期/Last Update: 1900-01-01