[1]梁文娜,李西海,胡柳,等.二至丸抑制绝经后骨质疏松大鼠骨代谢紊乱的作用机制研究[J].中医正骨,2017,29(11):1-7,14.
　LIANG Wenna,LI Xihai,HU Liu,et al.Study on mechanism of action of Erzhi Wan(二至丸)in inhibiting bone metabolism disorder in rats with postmenopausal osteoporosis[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2017,29(11):1-7,14.
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二至丸抑制绝经后骨质疏松大鼠骨代谢紊乱的作用机制研究()
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《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第29卷
期数:
2017年11期
页码:
1-7,14
栏目:
基础研究
出版日期:
2017-11-20

文章信息/Info

Title:
Study on mechanism of action of Erzhi Wan(二至丸)in inhibiting bone metabolism disorder in rats with postmenopausal osteoporosis
作者:
梁文娜; 李西海; 胡柳; 丁珊珊; 康洁; 王洋; 沈建英; 李灿东
福建中医药大学,福建 福州 350122
Author(s):
LIANG Wenna; LI Xihai; HU Liu; DING Shanshan; KANG Jie; WANG Yang; SHEN Jianying; LI Candong
Fujian University of Traditional Chinese Medicine,Fuzhou 350122,Fujian,China
关键词:
骨质疏松; 绝经后;  大鼠;  二至丸;  骨密度;  骨特异性碱性磷酸酶;  抗酒石酸酸性磷酸酶5b;  基质金属蛋白酶9;  组织蛋白酶K
Keywords:
Key words osteoporosis; postmenopausal;  rats;  Erzhi Pill;  bone density;  bone alkaline phosphotase;  tartrate-resistant acid phosphatase 5b;  matrix metalloproteinase 9;  cathepsin K
摘要:
目的:探讨二至丸抑制绝经后骨质疏松大鼠骨代谢紊乱的作用机制。方法:2月龄雌性清洁级SD大鼠60只,采用随机数字表随机分为假手术组15只与手术组45只。假手术组在双侧卵巢周围切除少许脂肪组织,手术组摘除双侧卵巢建立绝经后骨质疏松症大鼠模型。造模后2周,再将手术组大鼠随机分为模型组、二至丸组与雌二醇组,每组15只。二至丸组和雌二醇组大鼠,分别用二至丸混悬液和戊酸雌二醇片混悬液灌胃; 假手术组和模型组大鼠,用生理盐水灌胃; 每日1次,连续灌胃12周。药物干预结束后,采用ELISA法检测大鼠血清中骨代谢标记物骨特异性碱性磷酸酶(bone alkaline phosphotase,BALP)、抗酒石酸酸性磷酸酶-5b(tartrate-resistant acid phosphatase-5b,TRACP-5b)、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)、组织蛋白酶K(cathepsin K,Cath-K)含量; 并每组随机取3只大鼠的L5椎体,以4%多聚甲醛固定,行骨密度(bone mineral density,BMD)及组织学检测; 每组其余12只大鼠L5腰椎以液氮保存,行骨代谢标记物mRNA表达的检测。并对各组检测结果进行比较。结果:①BMD检测结果。药物干预12周后,4组间腰椎BMD检测结果比较,差异有统计学意义[(0.16±0.02)g·cm-2,(0.10±0.03)g·cm-2,(0.13±0.02)g·cm-2,(0.14±0.02)g·cm-2; F=5.800,P=0.005]; 假手术组、二至丸组与雌二醇组高于模型组(P=0.001,P=0.024,P=0.010); 假手术组与二至丸组、雌二醇组比较,差异无统计学意义(P=0.123,P=0.236); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.701)。②组织学检测结果。药物干预12周后,假手术组腰椎骨小梁致密,分布均匀,排列规则,表面光滑,交织成网状,骨小梁间隙均匀。模型组腰椎骨小梁变细、分布稀疏、散乱、不连续,表面粗糙,完整性差,出现碎片、断裂等。二至丸组与雌二醇组腰椎骨小梁变细,数量减少,分布稀疏,排列较规则。4组间骨小梁面积百分比比较,差异有统计学意义[(23.25±5.32)%,(11.82±3.87)%,(17.10±3.83)%,(18.08±2.59)%; F=8.144,P=0.001]; 模型组、二至丸组与雌二醇组低于假手术组(P=0.000,P=0.015,P=0.038); 二至丸组与雌二醇组高于模型组(P=0.034,P=0.014); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.677)。③骨代谢标记物血清含量检测结果。药物干预12周后,4组间血清BALP含量比较,差异有统计学意义[(58.14±9.04)单位·L-1,(40.91±6.47)单位·L-1,(51.13±7.88)单位·L-1,(52.23±7.41)单位·L-1; F=5.239,P=0.008]; 假手术组、二至丸组与雌二醇组高于模型组(P=0.001,P=0.034,P=0.012); 假手术组与二至丸组、雌二醇组比较,差异无统计学意义(P=0.133,P=0.286); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.645)。4组间血清TRACP-5b含量比较,差异有统计学意义[(0.71±0.13)pg·mL-1,(0.98±0.22)pg·mL-1,(0.79±0.09)pg·mL-1,(0.77±0.07)pg·mL-1; F=3.874,P=0.025]; 假手术组、二至丸组与雌二醇组低于模型组(P=0.004,P=0.038,P=0.022); 假手术组与二至丸组、雌二醇组比较,差异无统计学意义(P=0.320,P=0.459); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.795)。4组间血清MMP-9含量比较,差异有统计学意义[(1.63±0.23)pg·mL-1,(2.01±0.35)pg·mL-1,(1.64±0.25)pg·mL-1,(1.58±0.18)pg·mL-1; F=3.507,P=0.034]; 假手术组、二至丸组与雌二醇组低于模型组(P=0.021,P=0.023,P=0.009); 假手术组与二至丸组、雌二醇组比较,差异无统计学意义(P=0.972,P=0.699); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.673)。4组间血清Cath-K含量比较,差异有统计学意义[(2.55±0.40)pg·mL-1,(4.06±0.87)pg·mL-1,(3.07±0.77)pg·mL-1,(2.73±0.69)pg·mL-1; F=5.539,P=0.006]; 假手术组、二至丸组与雌二醇组低于模型组(P=0.001,P=0.024,P=0.004); 假手术组与二至丸组、雌二醇组比较,差异无统计学意义(P=0.217,P=0.671); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.408)。④骨代谢标记物mRNA表达检测结果。药物干预12周后,4组间BALPmRNA表达比较,差异有统计学意义[(1.01±0.04),(0.62±0.10),(0.78±0.13),(0.83±0.13); F=14.482,P=0.000]; 模型组、二至丸组与雌二醇组低于假手术组(P=0.000,P=0.001,P=0.007); 二至丸组与雌二醇组高于模型组(P=0.015,P=0.002),二至丸组与雌二醇组比较,差异无统计学意义(P=0.385)。4组间TRACP-5bmRNA表达比较,差异有统计学意义[(0.98±0.04),(2.05±0.41),(1.67±0.26),(1.50±0.21); F=16.574,P=0.000]; 模型组、二至丸组与雌二醇组高于假手术组(P=0.000,P=0.000,P=0.003); 二至丸组与雌二醇组低于模型组(P=0.024,P=0.002); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.282)。4组间MMP-9mRNA表达比较,差异有统计学意义[(1.00±0.06),(1.86±0.17),(1.51±0.32),(1.45±0.35); F=11.684,P=0.000]; 模型组、二至丸组与雌二醇组高于假手术组(P=0.000,P=0.002,P=0.007); 二至丸组与雌二醇组低于模型组(P=0.028,P=0.010); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.643)。4组间Cath-KmRNA表达比较,差异有统计学意义[(0.99±0.03),(2.52±0.57),(1.85±0.27),(1.74±0.54); F=13.543,P=0.000]; 模型组、二至丸组与雌二醇组高于假手术组(P=0.000,P=0.002,P=0.005); 二至丸组与雌二醇组低于模型组(P=0.011,P=0.004); 二至丸组与雌二醇组比较,差异无统计学意义(P=0.663)。结论:对于绝经后骨质疏松模型大鼠,二至丸和戊酸雌二醇片均可增加其骨密度和骨小梁数量; 作用机制可能是通过促进BALP表达、抑制TRACP-5b、MMP-9与Cath-K表达,从而抑制骨代谢紊乱; 两种药物的作用相当。
Abstract:
ABSTRACT Objective:To explore the mechanism of action of Erzhi Wan(二至丸,EZW)in inhibiting bone metabolism disorder in rats with postmenopausal osteoporosis(PMOP).Methods:Sixty 2-month-old clean-grade female SD rats were randomly divided into sham-operated group(15)and operation group(45)by using random digits table.The resection of fat around bilateral ovaries were performed on rats in sham-operated group,and the bilateral ovariectomy were performed on rats in operation group to build the PMOP rat models.At 2 weeks after the modeling,the rats in operation group were randomly subdivided into model group,EZW group and estradiol group,15 cases in each group.The rats in EZW group and estradiol group were intragastric administrated with EZW suspension and estradiol valerate suspension respectively,while the others in sham-operated group and model group were intragastric administrated with normal saline(NS),once a day for consecutive 12 weeks.After the end of drug intervention,the serum contents of bone alkaline phosphotase(BALP),tartrate-resistant acid phosphatase-5b(TRACP-5b),matrix metalloproteinase-9(MMP-9)and cathepsin K(Cath-K)were measured by using ELISA method.Three rats were randomly selected from each group and their L5 vertebraes were fetched out and fixed with 4% paraformaldehyde,and then the bone mineral density(BMD)detection and histological detection were performed.The L5 vertebraes of the other 12 rats in each group were preserved in liquid nitrogen,and the mRNA expression of bone metabolism marker were detected.The detection results were compared between the 4 groups.Results:After 12-week drug intervention,there was statistical difference in the detection result of lumbar vertebra BMD between the 4 groups(0.16+/-0.02,0.10+/-0.03,0.13+/-0.02,0.14+/-0.02 g/cm(2); F=5.800,P=0.005).The BMD were higher in sham-operated group,EZW group and estradiol group compared to model group(P=0.001,P=0.024,P=0.010).There was no statistical difference in the BMD between sham-operated group and EZW group and between sham-operated group and estradiol group(P=0.123,P=0.236),and there was no statistical difference in the BMD between EZW group and estradiol group(P=0.701).After 12-week drug intervention,the lumbar bone trabeculas of rats of sham-operated group were in a compact state and were uniformly distributed and regularly arranged,and they interlaced to form a netty structure with smooth surface and uniform interspace.The bone trabeculas of rats of model group became thin and were characterized by sparse,scattered and discontinuous distribution,and they presented with debris,rupture,rough surface and poor integrity.The bone trabeculas became thin and declined in number and characterized by sparse distribution and relatively regular arrangement in rats of EZW group and estradiol group.There was statistical difference in the area percentage of bone trabecula between the 4 groups(23.25+/-5.32,11.82+/-3.87,17.10+/-3.83,18.08+/-2.59%; F=8.144,P=0.001).The area percentage of bone trabecula was lower in model group,EZW group and estradiol group compared to sham-operated group(P=0.000,P=0.015,P=0.038),and was higher in EZW group and estradiol group compared to model group(P=0.034,P=0.014),and there was no statistical difference in the area percentage of bone trabecula between EZW group and estradiol group(P=0.677).After 12-week drug intervention,there was statistical difference in the serum contents of BALP between the 4 groups(58.14+/-9.04,40.91+/-6.47,51.13+/-7.88,52.23+/-7.41 unit/l; F=5.239,P=0.008).The serum contents of BALP were higher in sham-operated group,EZW group and estradiol group compared to model group(P=0.001,P=0.034,P=0.012).There was no statistical difference in the serum contents of BALP between sham-operated group and EZW group(P=0.133)and between sham-operated group and estradiol group(P=0.286)and between EZW group and estradiol group(P=0.645).There was statistical difference in the serum contents of TRACP-5b between the 4 groups(0.71+/-0.13,0.98+/-0.22,0.79+/-0.09,0.77+/-0.07 pg/ml; F=3.874,P=0.025).The serum contents of TRACP-5b were lower in sham-operated group,EZW group and estradiol group compared to model group(P=0.004,P=0.038,P=0.022),and there was no statistical difference in the serum contents of TRACP-5b between sham-operated group and EZW group(P=0.320)and between sham-operated group and estradiol group(P=0.459)and between EZW group and estradiol group(P=0.795).There was statistical difference in the serum contents of MMP-9 between the 4 groups(1.63+/-0.23,2.01+/-0.35,1.64+/-0.25,1.58+/-0.18 pg/ml; F=3.507,P=0.034).The serum contents of MMP-9 were lower in sham-operated group,EZW group and estradiol group compared to model group(P=0.021,P=0.023,P=0.009).There was no statistical difference in the serum contents of MMP-9 between sham-operated group and EZW group(P=0.972)and between sham-operated group and estradiol group(P=0.699)and between EZW group and estradiol group(P=0.673).There was statistical difference in the serum contents of Cath-K between the 4 groups(2.55+/-0.40,4.06+/-0.87,3.07+/-0.77,2.73+/-0.69 pg/ml; F=5.539,P=0.006).The serum contents of Cath-K were lower in sham-operated group,EZW group and estradiol group compared to model group(P=0.001,P=0.024,P=0.004).There was no statistical difference in the serum contents of Cath-K between sham-operated group and EZW group(P=0.217)and between sham-operated group and estradiol group(P=0.671)and between EZW group and estradiol group(P=0.408).After 12-week drug intervention,there was statistical difference in BALP mRNA expression between the 4 groups(1.01+/-0.04,0.62+/-0.10,0.78+/-0.13,0.83+/-0.13; F=14.482,P=0.000).The BALP mRNA expressions were lower in model group,EZW group and estradiol group compared to sham-operated group(P=0.000,P=0.001,P=0.007),and were higher in EZW group and estradiol group compared to model group(P=0.015,P=0.002),and there was no statistical difference in the BALP mRNA expression between EZW group and estradiol group(P=0.385).There was statistical difference in the TRACP-5b mRNA expression between the 4 groups(0.98+/-0.04,2.05+/-0.41,1.67+/-0.26,1.50+/-0.21; F=16.574,P=0.000).The TRACP-5b mRNA expressions were higher in model group,EZW group and estradiol group compared to sham-operated group(P=0.000,P=0.000,P=0.003),and were lower in EZW group and estradiol group compared to model group(P=0.024,P=0.002),and there was no statistical difference in the TRACP-5b mRNA expression between EZW group and estradiol group(P=0.282).There was statistical difference in the MMP-9 mRNA expression between the 4 groups(1.00+/-0.06,1.86+/-0.17,1.51+/-0.32,1.45+/-0.35; F=11.684,P=0.000).The MMP-9 mRNA expressions were higher in model group,EZW group and estradiol group compared to sham-operated group(P=0.000,P=0.002,P=0.007),and were lower in EZW group and estradiol group compared to model group(P=0.028,P=0.010),and there was no statistical difference in the MMP-9 mRNA expression between EZW group and estradiol group(P=0.643).There was statistical difference in Cath-K mRNA expression between the 4 groups(0.99+/-0.03,2.52+/-0.57,1.85+/-0.27,1.74+/-0.54; F=13.543,P=0.000).The Cath-K mRNA expressions were higher in model group,EZW group and estradiol group compared to sham-operated group(P=0.000,P=0.002,P=0.005),and were lower in EZW group and estradiol group compared to model group(P=0.011,P=0.004),and there was no statistical difference in the Cath-K mRNA expression between EZW group and estradiol group(P=0.663).Conclusion:For PMOP rat models,both EZW and estradiol valerate tablets can inhibit bone metabolism disorder through promoting the expression of BALP and inhibiting the expression of TRACP-5b,MMP-9 and Cath-K,which may be the mechanisms of action in increasing the BMD and the number of bone trabecula.The two drugs are similar to each other in curative effect.

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备注/Memo

备注/Memo:
基金项目:国家自然科学基金重点项目(81230087),福建省自然科学基金项目(2015J01339),福建省卫生系统中青年骨干人才培养项目(2015-ZQN-JC-32),福建省高校新世纪优秀人才支持计划项目(闽科教[2015]54号) 通讯作者:李灿东 E-mail:fjzylcd@126.com
更新日期/Last Update: 2018-04-02