[1]陈俊,吴广文,许惠凤,等.独活寄生汤含药血清对大鼠退变软骨细胞蛋白激酶 R样内质网激酶/免疫球蛋白结合蛋白信号通路的影响[J].中医正骨,2018,30(08):1-10.
　CHEN Jun,WU Guangwen,XU Huifeng,et al.Effect of Duhuo Jisheng Tang(独活寄生汤)medicated serum on protein kinase R-like endoplasmic reticulum kinase/immunoglobulin-binding protein signaling pathway in degenerated chondrocytes of rats[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2018,30(08):1-10.
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独活寄生汤含药血清对大鼠退变软骨细胞蛋白激酶 R样内质网激酶/免疫球蛋白结合蛋白信号通路的影响()
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《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第30卷
期数:
2018年08期
页码:
1-10
栏目:
基础研究
出版日期:
2018-08-20

文章信息/Info

Title:
Effect of Duhuo Jisheng Tang(独活寄生汤)medicated serum on protein kinase R-like endoplasmic reticulum kinase/immunoglobulin-binding protein signaling pathway in degenerated chondrocytes of rats
作者:
陈俊1; 吴广文2; 许惠凤2; 郑春松2; 戴一琛1; 邱建清1; 刘淑如1; 陈振沅1; 刘献祥2
1.福建中医药大学,福建 福州 350122; 2.福建省中西医结合老年性疾病重点实验室,福建 福州 350122
Author(s):
CHEN Jun1; WU Guangwen2; XU Huifeng2; ZHENG Chunsong2; DAI Yichen1; QIU Jianqing1; LIU Shuru1; CHEN Zhenyuan1; LIU Xianxiang2
1.Fujian University of Traditional Chinese Medicine,Fuzhou 350122,Fujian,China 2.Fujian Key Laboratory of Integrated Medicine on Geriatrics,Fuzhou 350122,Fujian,China
关键词:
骨关节炎;  软骨细胞;  独活寄生汤;  信号传导;  大鼠
Keywords:
osteoarthritis;  chondrocytes;  Duhuo Jisheng Tang;  signal transduction;  rats
摘要:
观察独活寄生汤含药血清对大鼠退变软骨细胞蛋白激酶R样内质网激酶(protein kinase R-like endoplasmic reticulum kinase,PERK)/免疫球蛋白结合蛋白(immunoglobulin-binding protein,BiP)信号通路的影响。方法:将36只2月龄清洁级雄性SD大鼠随机分为含药血清组和空白血清组,每组18只。含药血清组按照9.3 g·kg-1以独活寄生汤灌胃、空白血清组按照10 mL·kg-1以生理盐水灌胃,每天1次。连续灌胃7 d后,麻醉下行腹主动脉采血,获取独活寄生汤含药血清和空白血清。取4周龄SD大鼠膝关节,分离软骨进行软骨细胞培养,传代至第3代,以白细胞介素-1β干预24 h后获得退变软骨细胞。将获得的退变软骨细胞分为2组,分别以独活寄生汤含药血清(独活寄生汤组)和空白血清(空白组)进行干预。分别在干预24 h、48 h和72 h后,测定2组退变软骨细胞凋亡率、PERK mRNA含量、Bip mRNA含量、真核细胞翻译起始因子-2α(eukaryotic initiation factor 2α,eIF-2α)mRNA含量、转录激活因子-4(activating transcription factor 4,ATF-4)mRNA含量、生长抑制DNA损伤基因153抗原(growth arrest and DNA damage-inducible 153,GADD153)mRNA含量、半胱氨酸天冬氨酸蛋白酶(cysteine containing aspartate specific protease,Caspase)-9活性及Caspase-3活性。结果:①退变软骨细胞凋亡率。时间因素与分组因素存在交互效应(F=9.022,P=0.038)。2组软骨细胞凋亡率总体比较,差异有统计学意义,即存在分组效应(F=325.246,P=0.000); 干预后不同时点之间软骨细胞凋亡率的差异有统计学意义,即存在时间效应(F=389.768,P=0.000); 2组软骨细胞凋亡率随时间变化均呈降低趋势; 干预后各时点独活寄生汤组软骨细胞凋亡率均低于空白组(t=14.055,P=0.000; t=13.264,P=0.000; t=12.183,P=0.000)。②退变软骨细胞中PERK mRNA含量。时间因素与分组因素不存在交互效应(F=3.002,P=0.157); 独活寄生汤组软骨细胞中PERK mRNA含量总体低于空白组,即存在分组效应(F=17.833,P=0.013); 干预后不同时点之间软骨细胞中PERK mRNA含量的差异有统计学意义,即存在时间效应(F=43.060,P=0.003); 2组软骨细胞中PERK mRNA含量随时间变化均呈降低趋势。③退变软骨细胞中Bip mRNA含量。时间因素与分组因素不存在交互效应(F=4.092,P=0.106); 独活寄生汤组软骨细胞中Bip mRNA含量总体低于空白组,即存在分组效应(F=15.136,P=0.018); 干预后不同时点之间软骨细胞中Bip mRNA含量的差异有统计学意义,即存在时间效应(F=62.968,P=0.001); 2组软骨细胞中Bip mRNA含量随时间变化均呈降低趋势。④退变软骨细胞中eIF-2α mRNA含量。时间因素与分组因素不存在交互效应(F=2.138,P=0.201); 独活寄生汤组软骨细胞中eIF-2α mRNA含量总体低于空白组,即存在分组效应(F=155.852,P=0.000); 干预后不同时点之间软骨细胞中eIF-2α mRNA含量的差异有统计学意义,即存在时间效应(F=50.328,P=0.000); 2组软骨细胞中eIF-2α mRNA含量随时间变化均呈降低趋势,且降低趋势基本一致。⑤退变软骨细胞中ATF-4 mRNA含量。时间因素与分组因素存在交互效应(F=14.612,P=0.017); 2组软骨细胞中ATF-4 mRNA含量总体比较,组间差异有统计学意义,即存在分组效应(F=33.703,P=0.004); 干预后不同时点之间软骨细胞中ATF-4 mRNA含量的差异有统计学意义,即存在时间效应(F=187.700,P=0.000); 2组软骨细胞中ATF-4 mRNA含量随时间变化均呈降低趋势; 干预后各时点独活寄生汤组软骨细胞中ATF-4 mRNA含量均低于空白组(t=4.343,P=0.012; t=3.915,P=0.017; t=10.719,P=0.000)。⑥退变软骨细胞中GADD153 mRNA含量。时间因素与分组因素不存在交互效应(F=3.053,P=0.116); 独活寄生汤组软骨细胞中GADD153 mRNA含量总体低于空白组,即存在分组效应(F=16.946,P=0.015); 干预后不同时点之间软骨细胞中GADD153 mRNA含量的差异有统计学意义,即存在时间效应(F=88.206,P=0.000); 2组软骨细胞中GADD153 mRNA含量随时间变化均呈降低趋势。⑦退变软骨细胞中Caspase-9活性。时间因素与分组因素不存在交互效应(F=1.266,P=0.327); 独活寄生汤组软骨细胞中Caspase-9活性总体低于空白组,即存在分组效应(F=21.164,P=0.010); 干预后不同时间点之间软骨细胞中Caspase-9活性的差异有统计学意义,即存在时间效应263.384,P=0.000); 2组软骨细胞中Caspase-9活性随时间变化均呈降低趋势,且降低趋势基本一致。⑧退变软骨细胞中Caspase-3活性。时间因素与分组因素不存在交互效应(F=1.346,P=0.314); 独活寄生汤组软骨细胞中Caspase-3活性总体低于空白组,即存在分组效应(F=19.422,P=0.012); 干预后不同时间点之间软骨细胞中Caspase-3活性的差异有统计学意义,即存在时间效应(F=130.649,P=0.000); 2组软骨细胞中Caspase-3活性随时间变化均呈降低趋势,且降低趋势基本一致。结论:独活寄生汤含药血清可通过调控大鼠退变软骨细胞PERK/Bip信号通路,抑制因内质网应激反应引起的软骨细胞凋亡。
Abstract:
To observe the effect of Duhuo Jisheng Tang(独活寄生汤,DHJST)medicated serum on protein kinase R-like endoplasmic reticulum kinase(PERK)/immunoglobulin-binding protein(BiP)signaling pathway in degenerated chondrocytes of rats.Methods:Thirty-six 2-month-old clean-grade male SD rats were randomly divided into medicated serum group and blank serum group,18 rats in each group.The rats in medicated serum group were intragastric administrated with DHJST in dosage of 9.3 g/kg,while the others in blank serum group were intragastric administrated with the normal saline in dosage of 10 mL/kg,once a day for consecutive 7 days.After the last intragastric administration,their blood were fetched out from abdominal aorta under anesthesia and were made into DHJST medicated serum and blank serum respectively.The knee joints of 4-week-old SD rats were fetched out and the chondrocytes were isolated from knee articular cartilage and were cultured.The third-generation chondrocytes were intervented by interleukin-1β(IL-1β)for 24 hours and then the degenerated chondrocytes were obtained.The obtained degenerated chondrocytes were divided into 2 groups and were intervened by DHJST medicated serum(DHJST group)and blank serum(blank group)respectively.The degenerated chondrocytes apoptosis rate,the contents of PERK mRNA,Bip mRNA,eukaryotic initiation factor 2α(eIF-2α)mRNA,activating transcription factor 4(ATF-4)mRNA and growth arrest and DNA damage-inducible 153(GADD153)mRNA and the activities of cysteine containing aspartate specific protease(Caspase)-9 and Caspase-3 in degenerated chondrocytes were detected at 24,48 and 72 hours after the intervention respectively.Results:There was interaction between time factor and group factor in degenerated chondrocytes apoptosis rate(F=9.022,P=0.038).There was statistical difference in degenerated chondrocytes apoptosis rate between the 2 groups in general,in other words,there was group effect(F=325.246,P=0.000).There was statistical difference in chondrocytes apoptosis rate between different timepoints after the intervention,in other words,there was time effect(F=389.768,P=0.000).The chondrocytes apoptosis rate presented a time-dependent decreasing trend in both of the 2 groups.The chondrocytes apoptosis rate was lower in DHJST group compared to blank group at different timepoints after intervention(t=14.055,P=0.000; t=13.264,P=0.000; t=12.183,P=0.000).There was no interaction between time factor and group factor in the content of PERK mRNA in degenerated chondrocytes(F=3.002,P=0.157).The content of PERK mRNA in chondrocytes was lower in DHJST group compared to blank group in general,in other words,there was group effect(F=17.833,P=0.013).There was statistical difference in content of PERK mRNA in chondrocytes between different timepoints after intervention,in other words,there was time effect(F=43.060,P=0.003).The content of PERK mRNA in chondrocytes presented a time-dependent decreasing trend in both of the 2 groups.There was no interaction between time factor and group factor in the content of Bip mRNA in degenerated chondrocytes(F=4.092,P=0.106).The content of Bip mRNA in chondrocytes was lower in DHJST group compared to blank group in general,in other words,there was group effect(F=15.136,P=0.018).There was statistical difference in content of Bip mRNA in chondrocytes between different timepoints after intervention,in other words,there was time effect(F=62.968,P=0.001).The content of Bip mRNA in chondrocytes presented a time-dependent decreasing trend in both of the 2 groups.There was no interaction between time factor and group factor in the content of eIF-2α mRNA in degenerated chondrocytes(F=2.138,P=0.201).The content of eIF-2α mRNA in chondrocytes was lower in DHJST group compared to blank group in general,in other words,there was group effect(F=155.852,P=0.000).There was statistical difference in content of eIF-2α mRNA in chondrocytes between different timepoints after intervention,in other words,there was time effect(F=50.328,P=0.000).The content of eIF-2α mRNA in chondrocytes presented a time-dependent decreasing trend in both of the 2 groups,and the 2 groups were consistent with each other in the decreasing trend of content of eIF-2α mRNA in chondrocytes.There was interaction between time factor and group factor in the content of ATF-4 mRNA in degenerated chondrocytes(F=14.612,P=0.017).There was statistical difference in content of ATF-4 mRNA in chondrocytes between the 2 groups in general,in other words,there was group effect(F=33.703,P=0.004).There was statistical difference in content of ATF-4 mRNA in chondrocytes between different timepoints after intervention,in other words,there was time effect(F=187.700,P=0.000).The content of ATF-4 mRNA in chondrocytes presented a time-dependent decreasing trend in both of the 2 groups.The content of ATF-4 mRNA in chondrocytes was lower in DHJST group compared to blank group at different timepoints after intervention(t=4.343,P=0.012; t=3.915,P=0.017; t=10.719,P=0.000).There was no interaction between time factor and group factor in content of GADD153 mRNA in degenerated chondrocytes(F=3.053,P=0.116).The content of GADD153 mRNA in chondrocytes was lower in DHJST group compared to blank group in general,in other words,there was group effect(F=16.946,P=0.015).There was statistical difference in content of GADD153 mRNA in chondrocytes between different timepoints after intervention,in other words,there was time effect(F=88.206,P=0.000).The content of GADD153 mRNA in chondrocytes presented a time-dependent decreasing trend in both of the 2 groups.There was no interaction between time factor and group factor in the activity of Caspase-9 in degenerated chondrocytes(F=1.266,P=0.327).The activity of Caspase-9 in chondrocytes was lower in DHJST group compared to blank group in general,in other words,there was group effect(F=21.164,P=0.010).There was statistical difference in activity of Caspase-9 in chondrocytes between different timepoints after intervention,in other words,there was time effect(F=263.384,P=0.000).The activity of Caspase-9 in chondrocytes presented a time-dependent decreasing trend in both of the 2 groups,and the 2 groups were consistent with each other in the decreasing trend of activity of Caspase-9 in chondrocytes.There was no interaction between time factor and group factor in activity of Caspase-3 in degenerated chondrocytes(F=1.346,P=0.314).The activity of Caspase-3 in chondrocytes was lower in DHJST group compared to blank group in general,in other words,there was group effect(F=19.422,P=0.012).There was statistical difference in activity of Caspase-3 in chondrocytes between different timepoints after intervention,in other words,there was time effect(F=130.649,P=0.000).The activity of Caspase-3 in chondrocytes presented a time-dependent decreasing trend in both of the 2 groups,and the 2 groups were consistent with each other in the decreasing trend of activity of Caspase-3 in chondrocytes.Conclusion:DHJST medicated serum can inhibit the chondrocyte apoptosis caused by endoplasmic reticulum stress reaction through regulating PERK/BiP signaling pathway in the degenerated chondrocytes of rats.

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备注/Memo

备注/Memo:
基金项目:国家自然科学基金项目(81573801); 福建省自然科学基金杰青项目(2017J06018); 福建省卫生计生科研人才培养项目(2017-ZQN-62) 通讯作者:刘献祥 E-mail:liuxianxiang@163.com
更新日期/Last Update: 2018-08-31