摘要
目的
研究体现补益肝肾与化瘀通络治法的复元胶囊及其活性成分对退行性骨关节炎关节软骨基质降解的保护作用,并从uPA系统、IκBα-NF-κB信号途径的角度探讨其作用机制。
方法
1新西兰大白兔48只,随机分为正常组、模型组、盐酸氨基葡萄糖胶囊组及复元胶囊低、中、高剂量组6组,每组8只。采用膝关节石膏制动法结合d-半乳糖30 mg/kg/d皮下注射6周建立兔衰老骨关节炎模型,造模当日即开始治疗,正常组、模型组予生理盐水10ml,盐酸氨基葡萄糖组剂量为90 mg/kg/d,复元胶囊低、中、高剂量组剂量分别为1350 mg/kg/d,2700 mg/kg/d,5400 mg/kg/d,灌胃,1次/日,连续10周。HE染色关节软骨Mankin’s评分,免疫组化学染色法检测软骨组织中尿激酶型纤溶酶原激活物(uPA)及其特异性受体(uPAR)和抑制剂(PAI)的表达,Western检测各组软骨组织中uPA、NF-κB的表达。
2于24孔板中培养兔软骨组织,分为空白组、20%空白血清组、TNF-α模型组、uPA抑制剂阿米洛利组、5%、10%、20%复元胶囊含药血清组共7组。除空白组,各组均加入TNF-α10 ug/L诱导软骨组织基质降解, 1 h后,按实验分组加药。采用1,9-二甲基亚甲蓝法检测各组培养上清中氨基聚糖(GAG)的含量,以评价软骨基质中蛋白多糖降解的情况。采用碱水解法检测各组培养上清中羟脯氨酸(Hyp)释放的量,以评价软骨基质中胶原降解的情况。
3原代培养兔软骨细胞,MTT检测各组软骨细胞活性,筛选药物最佳作用浓度,分为7组:空白组、TNF-α模型组、盐酸氨基葡萄糖25 mg/m1组、20%复元胶囊含药血清组、淫羊藿苷12.5μg/ml组、三七皂苷R1 125μg/ml组、淫羊三七组(淫羊藿苷12.5μg/ml+三七皂苷125μg/ml)组, RT-PCR检测各组uPA、NF-κB(P65) mRNA的含量,EMSA检测NF-κB(P65)与DNA结合的活性,Western检测IκBα水平。
结果
1复元胶囊治疗兔骨关节炎10周后,各组病理Mankin’s评分分别为模型组8. 73±0. 94,盐酸氨基葡萄糖组3. 46±0.78,复元胶囊高剂量组3. 28±0. 46。结果显示复元胶囊可改善兔骨关节炎软骨病变,复元胶囊高剂量与模型组比较差异有显著性(P<0.01),与盐酸氨基葡萄糖组比较差异无显著性(P>0.05)。
免疫组化显示uPA、uPAR及PAI阳性表达定位于软骨细胞的细胞质,呈黄色或棕黄色颗粒。模型组中uPA、uPAR及PAI阳性细胞率分别为79.61±2.78,60.55±1.35,52.33±2.87,盐酸氨基葡萄糖组为35.38±2.31 , 30.4±1.34 , 72.35±1.52 ,复元胶囊高剂量组分别为36.45±1.35,31.35±1.18,66.57±1.25,结果显示复元胶囊高剂量治疗后uPA及uPAR降低,PAI升高,与模型组比较差异有显著性(P<0.01),与盐酸氨基葡萄糖组比较差异无显著性(P>0.05)。
Western blot检测结果,模型组uPA/GAPDH、NF-κB/GAPDH为1.13692±0.2451,0.89828±0.1650,盐酸氨基葡萄糖组为0.25147±0.0537,0.36386±0.0458,复元胶囊高剂量组为0.26003±0.0427,0.25315±0.0336,结果提示复元胶囊高剂量组能显著降低兔关节软骨中uPA、NF-κB表达,与模型组比较差异有显著性(P<0.01),复元胶囊中、高剂量组对NF-κB的抑制作用强于盐酸氨基葡萄糖组(P<0.05)。
2复元胶囊对兔软骨组织块基质分解代谢产物GAG、Hyp的研究显示,空白组仅有微量释放,分别为1.32±0.18,0.05±0.01,TNF-α模型组则有显著释放,分别为4.76±0.39,0.89±0.07,两组比较差异有显著性(P<0.01)。uPA抑制剂阿米洛利组GAG、Hyp含量分别为1.85±0.21,0.41±0.06,20%复元胶囊含药血清组分别为2.92±0.34,0.64±0.07。结果显示,复元胶囊有一定抑制软骨基质中蛋白多糖及胶原降解的作用,20%复元胶囊含药血清组GAG、Hyp的释放较TNF-α模型组显著降低(P<0.01),但作用弱于阿米洛利(P<0.01)。
3复元胶囊及其主要成份对兔软骨细胞实验,MTT法检测各组兔关节软骨细胞活性结果显示,复元胶囊含药血清、淫羊藿苷、三七皂苷R1、淫羊藿苷+三七皂苷R1均能促进软骨细胞增殖活性,以48 h时作用最明显,与空白组比较差异有统计学意义(P<0.01 ),复元胶囊含药血清组作用最强,优于阳性对照盐酸氨基葡萄糖组(p<0.05)。
RT-PCR实验显示,空白组uPA、NF-κB(p65)mRNA表达量分别为0.225±0.016,0.202±0.014,TNF-α模型组为0.429±0.018,0.463±0.021,较空白组明显升高(P<0.01)。盐酸氨基葡萄糖组、复元胶囊含药血清组、淫羊藿苷组、三七皂苷R1组、淫羊藿苷+三七皂苷R1组uPA mRNA的表达分别为0242±0.019,0.254±0.012,0.273±0.013,0.247±0.015,0.236±0.014 ; NF-κB ( p65 ) mRNA的表达分别为0.243±0.017 ,0.229±0.012,0.281±0.011,0.262±0.015,0.232±0.014。结果表明,各实验用药组都能显著降低uPA、NF-κB(P65) mRNA水平,与TNF-α模型组比较有显著差异(P<0.01),但各给药组间无明显差异(P>0. 05)。
EMSA实验检测NF-κB(p65)与DNA的结合活性结果显示,空白组结合电泳条带光密度A值为47.72±8.19 , TNF-α模型组为141.25±31.83,较空白组显著升高(P<0.01)。盐酸氨基葡萄糖组、复元胶囊含药血清组、淫羊藿苷组、三七皂苷R1组、淫羊藿苷+三七皂苷R1组分别为84.28±19.04、52.85±11.42、86.66±35.23、91.15±28.67、71.47±10.57,反映各药物组细胞内NF-κB(p65)与DNA的结合活性均不同程度下降,与TNF-α模型组比较差异有统计学意义(P<0.01),其中复元胶囊含药血清组作用最强,淫羊藿苷+三七皂苷R1组显示协同效应,均优于阳性对照盐酸氨基葡萄糖组(P<0.01),复元胶囊含药血清组作用优于淫羊藿苷+三七皂苷R1组(P<0.01)。
Western blot检测各组IκBα的表达,空白组IκBα表达量为0.348±0.025,TNF-α模型组为0.374±0.032,与空白组无显著差异(P>0.05)。盐酸氨基葡萄糖组、复元胶囊含药血清组、淫羊藿苷组、三七皂苷R1组、淫羊藿苷+三七皂苷R1组IκBα的表达分别为0.739±0.028,0.763±0.021,0.824±0.035,0.793±0.024,0.832±0.023,与模型组比较明显升高(P<0.01)。各中药组与盐酸氨基葡萄糖组比较差异无显著性(P>0.05)。
结论
1复元胶囊可明显改善兔骨关节病理改变,降低Mankin’s评分。复元胶囊能显著降低兔关节软骨中uPA、uPAR、NF-κB的表达,明显升高PAI的表达。提示复元胶囊可能通过调控uPA系统对骨关节炎发挥防治作用。
2复元胶囊含药血清对兔软骨组织块GAG、Hyp有明显下调作用,表明复元胶囊具有一定抑制软骨基质中蛋白多糖及胶原降解的作用。
3复元胶囊及其主要成份淫羊藿苷、三七皂苷R1均能促进软骨细胞增殖活性,显著降低uPA、NF-κB(P65) mRNA水平,降低NF-κB(p65)与DNA的结合活性,升高细胞内IκBα水平。提示复元胶囊及其主要成份可能通过升高IκBα水平,降低NF-κB (P65)的活性,从而降低uPA的表达,保护软骨细胞免受炎症因子的损伤。
Objective
To study the protective effects of FuYuan capsule and its two main active ingredients, which introduced the therapy of nourishing liver and kidney also resolving stasis and dredging collaterals, on the extracellular matrix of osteoarthritis. To illuMinate its molecular mechanism through the urokinase-type plasminogen activator (uPA)systerm and IκBα-NF-κB signaling pathway.
Methods
1 Forty-eight New Zealand rabbits were divided into 6 groups randomly, 8 rabbits in each group : normol group and model group(saline10ml/d),Glucosamine hydrochloride (90mg/kg/d), Fyc low dose group(1350 mg/kg/d),middle dose group (2700 mg/kg/d) and high dose group (5400 mg/kg/d).Rabbit osteoarthritis model was induced by combined treatment of D-galactose injection in dose of 30mg/kg/d and plaster immobilization,for 6周eeks . Rabbits were treated according to grouping at the same day of modeling, gavage , daily , for 10周eeks. Morphology of cartilage were detected by light microscope and HE staining.Then cartilage sections were analyzed by immunohistochemistry to test uPA,uPAR and PAI. The expresss of uPA、NF-κB were analyzed by Western blotting .
2 Rabbit cartilage tissues were cultured in 24 well comboplate , divided into blank group, 20% blank seruM group, TNF-αmodel group(10 ug / L,1h), uPA inhibitor amiloride group 0.5mmol / L, 5%, 10%, 20% Fyc containing seruM groups. Except the blank group, each group was stimulated by TNF-α(10 ug / L,1h) to induce the cartilage matrix degradation. Then disposed according to grouping. glycosaminoglycan(GAG) that had been released into the mediuM were measured by 1,9-dimethylmethylene blue method to evaluate the extent of proteoglycan degradation. Hydroxyproline that had been released into the mediuM were measured by alkali hydrolyzation method to evaluate the extent of collagen degradation.
3 Rabbit cartilage cells were cultured for experimentation and its activity were detected by MTT. According to the result of MTT, 7 groups were divided: blank group, TNF-αmodel group, Glucosamine hydrochloride (25 mg/m1) group,20% FuYuan capsule seruM containing group,Icariin group (12.5μg/ml),arasaponin R1 group (125μg/ml),Icariin (12.5μg/ml) combined arasaponin R1 (125μg/ml) group. The content of uPA, NF-κB(p65) mRNA were determined by reverse transcription polymerase chain reaction (RT-PCR). The activities of NF-κB(P65) combined DNA were determined by electrophoretic mobility shift assays (EMSA). IκBαwere detected by Western blotting.
Results
1 After treatment of OA model 10 weeks, analyse Mankin’s score of each group. Model group was 8.73±0. 94, Glucosamine hydrochloride group was 3.46±0.78, Fyc high administration was 3.28±0.46. Fyc high administration could markedly decrease the pathological damage. There were significant differences in Mankin’s score among high dose FuYuan capsule and model group (P<0.01), not worse than the Glucosamine hydrochloride group(P>0. 05).
Immunohistochemical staining indicated that the expression intensities and positive cell ratio of uPA, uPAR and PAI increased in OA group 79.61±2.78 , 60.55±1.35 , 52.33±2.87 compared with the model group(P<0.01), while FuYuan capsule treatment could reduce uPA 36.45±1.35 and uPAR 31.35±1.18 expression with the best effect in high dose group(P<0.01). PAI 66.57±1.25 decreased after FuYuan capsule treatment( P<0.01 ) . Not worse than the Glucosamine hydrochloride group 35.38±2.31,30.4±1.34,72.35±1.52(P>0.05).
Western blot test results show that the uPA/GAPDH, NF-κB/GAPDH in model group were 1.13692±0.2451,0.89828±0.1650,which in glucosamine hydrochloride group were 0.25147±0.0537,0.36386±0.0458, in Fuyuan capsule group of high-dose were 0.26003±0.0427,0.25315±0.0336. These results indicate that the expresssion of uPA、NF-κB were reduce significantly after high dose FuYuan capsule treatment(P<0.01). The inhibiting effect to NF-κB in middle and high dose FuYuan capsule is better than the Glucosamine hydrochloride group(P<0. 05)。
2 The study of rabbit cartilage tissue matrix degradation metabolites GAG, Hyp shows that blank group were 1.32±0.18,0.05±0.01,TNF-αmodel group were 4.76±0.39, 0.89±0.07, increased significantly than blank group (P <0.01). The contents of GAG and Hyp in uPA inhibitor amiloride group were 4.69±0.30,0.41±0.06, in glucosamine hydrochloride group were 3.15±0.59,0.72±0.13, which in 20% FuYuan capsule containing seruM group were 2.92±0.34, 0.64±0.07, all significantly decrease compared with the model group (P <0.01). The results suggest that FuYuan capsule could inhibite the cartilage matrix proteoglycan and collagen degradati in osteoarthritis chondrocytes.
3 MTT showed that FuYuan capsule, icariin ,arasaponin R1 ,icariin and arasaponin R1 could significantly promote proliferation of cartilage cells in 48h compared with blank control group (P<0.01). FuYuan capsule group were better than the glucosamine hydrochloride group(P<0.05).
RT-PCR showed that uPA, NF-κB(p65)mRNA expression in blank group were 0.225±0.016,0.202±0.014,while in TNF-αgroup were 0.429±0.018,0.463±0.021 which increased significantly compared with blank group(P<0.01)The uPA, mRNA expression of above remedy groups were 0242±0.019,0.254±0.012,0.273±0.013,0.247±0.015,0.236±0.014, NF-κB(p65)mRNA were 0.243±0.017,0.229±0.012,0.281±0.011,0.262±0.015,0.232±0.014 which indicate that the expresssion of uPA, NF-κB(p65)mRNA were reduced significantly than the TNF-αgroup(P<0.01). There were no significant difference among each remedy group.(P>0. 05).
EMSA to evaluate the binding activity between NF-κB(p65)and DNA showed that absorbance value in blank group were 47.72±8.19, while in TNF-αgroup were 141.25±31.83,which increased significantly when compared with blank group(P<0.01).The absorbance value in remedy groups were 84.28±19.04,52.85±11.42,86.66±35.23,91.15±28.67,71.47±10.57 respectively,which indicate that FuYuan capsule containing seruM group has the best effect, compared with the TNF-αgroup and Icariin combined arasaponin R1 group(P<0.01). Icariin combined arasaponin R1 group show synergistic effect, compared with the TNF-αgroup(P<0.01).
Western Blotting was performed to evaluate the extent of IκBα. There was no significant difference between TNF-αgroup and blank group(P>0.05). While glucosamine hydrochloride, Fyc, icariin, arasaponin R1, and icariin combined with arasaponin R1 group could significantly increase the extent of IκBα, which respectively reached 0.739±0.028,0.763±0.021,0.824±0.035,0.793±0.024,0.832±0.023, than TNF-αgroup 0.374±0.032(P<0. 05 or P<0.01),but no significant difference among all treatment groups(P>0. 05).
Conclusions
1 Fuyuan capsule can significantly improve pathological changes in OA rabbit model and lower Mankin’s ' s score. FuYuan capsule could reduce the expression of uPA and uPAR while increase PAI in cartilage cells of experimental osteoarthritis of rabbits, which maybe potential mechanisms underlying the effect of FuYuan capsule for OA.
2 FuYuan capsule containing seruM can significantly decrease the expression of GAG and Hyp in rabbit cartilage tissue. FuYuan capsule could inhibite the degradation of collagen and proteoglycan in the cartilage matrix.
3 FuYuan capsule and its two main active ingredients, icariin and arasaponin R1 could protect chondrocytes from damage through increasing the express of IκBα, inhibiting the NF-κB(P65) activity,and then reducing the expresssion of uPA.
引文
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