杜仲醇提取物可促进根尖周炎模型大鼠骨组织的愈合

doi:10.3969/j.issn.2095-4344.2727

中国组织工程研究 ›› 2020, Vol. 24 ›› Issue (23): 3685-3689.doi: 10.3969/j.issn.2095-4344.2727

• 口腔组织构建 oral tissue construction • 上一篇下一篇

杜仲醇提取物可促进根尖周炎模型大鼠骨组织的愈合

吴大雷¹，周守恒¹，闫健伟¹，李博¹，许诺²，史春³，高阳⁴

¹大连医科大学附属第二医院口腔科，辽宁省大连市 116027；²大连医科大学中山学院，辽宁省大连市 116000；³大连医科大学口腔医学院，辽宁省大连市 116000；⁴大连市友谊医院口腔科，辽宁省大连市 116000

收稿日期:2019-09-10 修回日期:2019-09-11 接受日期:2019-10-15 出版日期:2020-08-18 发布日期:2020-04-25
通讯作者: 高阳，硕士，副主任医师，大连市友谊医院口腔科，辽宁省大连市 116000
作者简介:吴大雷，男，1981年生，硕士，主治医师，主要从事口腔科方面的研究。
基金资助:
辽宁省自然科学基金(20180550563)

Alcohol extract of Eucommia ulmoides Oliv. promotes bone healing in rats with periapical periodontitis

Wu Dalei¹, Zhou Shouheng¹, Yan Jianwei¹, Li Bo¹, Xu Nuo², Shi Chun³, Gao Yang⁴

¹Department of Stomatology, Second Affiliated Hospital of Dalian Medical University; ²Zhongshan College of Dalian Medical University; ³School of Stomatology, Dalian Medical University; ⁴Department of Stomatology, Dalian Friendship Hospital Stomatology

Received:2019-09-10 Revised:2019-09-11 Accepted:2019-10-15 Online:2020-08-18 Published:2020-04-25
Contact: Gao Yang, Master, Associate chief physician, Department of Stomatology, Dalian Friendship Hospital Stomatology, Dalian 116000, Liaoning Province, China
About author:Wu Dalei, Master, Attending physician, Department of Stomatology, Second Affiliated Hospital of Dalian Medical University, Dalian 116027, Liaoning Province, China
Supported by:
the Natural Science Foundation of Liaoning Province, No. 20180550563

摘要/Abstract

摘要：

文题释义：

杜仲：杜仲是中国传统的中药药材，其具有增加机体免疫性、强身健骨的疗效，研究表明杜仲可以促进成骨细胞的增殖并且可以促进骨组织的愈合。近年来对于杜仲的研究主要集中于其有效成分的提取及分析。

杜仲醇：是杜仲的主要有效成分之一，可以增强关节炎大鼠骨组织的强度，并且具有降血压以及促进伤口愈合的能力。

背景：目前关于杜仲的研究主要集中于其治疗骨关节炎能增强骨组织的愈合能力，但是关于杜仲对根尖周炎骨破坏的修复作用尚未见报道。

目的：探讨杜仲醇提取物对根尖周炎大鼠组织蛋白酶K的影响。

方法：选取24只SD大鼠随机分为根尖周炎组20只及对照组4只，根尖周炎组于右侧下颌第一磨牙开髓后建立根尖周炎模型，对照组不做任何处理。饲养4周后，取根尖周炎组及对照组各4只拍摄MICRO-CT，计算根尖周炎骨破坏量，确认大鼠根尖周炎动物模型构建成功。饲养第5周，将剩余16只根尖周炎大鼠随机分为杜仲醇提取物组及生理盐水组，每组8只，每天灌胃杜仲醇提取物5 mL/kg或等量生理盐水。灌胃4周后，每组取4只大鼠拍摄MICRO-CT，分析杜仲醇提取物对根尖周骨组织的修复能力，另外取4只大鼠采用免疫组化染色观察右下颌第一磨牙牙槽骨组织蛋白酶K的表达。

结果与结论：①MICRO-CT结果显示，对照组骨吸收体积为(0.223±0.009) mm³，根尖周炎组骨吸收体积为(0.945±0.037) mm³，两组骨吸收量比较差异有显著性意义(P=0.00)，说明大鼠根尖周炎模型构建成功；②灌胃4周后，MICRO-CT结果显示杜仲醇提取物组骨吸收体积较灌胃前减小，差异有显著性意义(P < 0.05)；③灌胃4周后，免疫组化结果显示杜仲醇提取物根尖周炎骨破坏标志因子组织蛋白酶K的表达较灌胃前降低，差异有显著性意义(P < 0.05)；④结果表明，杜仲醇提取物可以抑制骨破坏标志因子组织蛋白酶K的表达，并且可以促进大鼠根尖周炎骨组织的愈合。

ORCID: 0000-0001-5450-7016(吴大雷)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 杜仲, 根尖周炎, 动物模型, 组织蛋白酶K, MICO-CT, 免疫组化

Abstract:

BACKGROUND: Current research on Eucommia ulmoides Oliv. mainly focuses on its use in the treatment of osteoarthritis that Eucommia ulmoides Oliv. can enhance the healing ability of bone tissue. However, research on its bone repair ability in periapical periodontitis has not been reported.

OBJECTIVE: To study the effect of alcohol extract of Eucommia ulmoides Oliv. on cathepsin K expression in periapical periodontitis rats.

METHODS: Twenty-four Sprague-Dawley rats were divided into normal control group (n=4) and apical periodontitis group (n=20). In the periapical periodontitis group, a periapical periodontitis model was established after exposure of the dental pulp in the first molar of the right mandible. The normal control group did not deal with any treatment. After 4 weeks of feeding, four rats from each group were taken for micro-CT detection. Bone destruction was quantified to confirm whether the rat model of periapical periodontitis was successfully constructed. After 5 weeks of feeding, the remaining 16 rats with periapical periodontitis were equally randomized into alcohol extract group (given alcohol extract of Eucommia ulmoides Oliv. via intragastric administration, 5 mL/kg per day) and normal saline group (given the same dose of normal saline via intragastric administration every day). After 4 weeks of gavage, four mice from each group were selected to perform micro-CT examination. The ability of alcohol extract of Eucommia ulmoides Oliv. to repair periapical bone tissue was analyzed. First molars of the right mandible from the other four rats in each group were extracted to detect the expression of cathepsin K in the alveolar bone using immunohistochemical staining.

RESULTS AND CONCLUSION: Micro-CT results showed that the rat model of periapical periodontitis was successfully constructed as there was a significant difference in the bone resorption volume between the normal control and apical periodontitis groups [(0.223±0.009) mm³ vs. (0.945±0.037) mm³, P=0.00]. After 4 weeks of gavage, the micro-CT results showed that the alcohol extract of Eucommia ulmoides Oliv. significantly reduced the bone resorption volume in the rat model of periapical periodontitis (P < 0.05). Immunohistochemistry results showed that the alcohol extract of Eucommia ulmoides Oliv. significantly inhibited the expression of cathepsin K, a marker of bone destruction, in the rat model of periapical periodontitis. Therefore, these findings indicate that the alcohol extract of Eucommia ulmoides Oliv. can inhibit the expression of cathepsin K and promote the healing of bone tissue in the rats with periapical periodontitis.

Key words: Eucommia ulmoides Oliv, periapical periodontitis, animal model, cathepsin K, micro-CT, immunohistochemistry

中图分类号:

吴大雷, 周守恒, 闫健伟, 李博, 许诺, 史春, 高阳. 杜仲醇提取物可促进根尖周炎模型大鼠骨组织的愈合[J]. 中国组织工程研究, 2020, 24(23): 3685-3689.

Wu Dalei, Zhou Shouheng, Yan Jianwei, Li Bo, Xu Nuo, Shi Chun, Gao Yang. Alcohol extract of Eucommia ulmoides Oliv. promotes bone healing in rats with periapical periodontitis[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(23): 3685-3689.

图/表（结果） 3

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引言

材料方法

1.1 设计随机对照动物实验。

1.2 时间及地点 2018年5月至2019年5月在大连医科大学附属第二医院完成。

1.3 材料杜仲(北京同仁堂有限责任公司)；甲醇、生理盐水(上海生工)；电动牙钻机(日进齿科材料有限公司)；MICRO-CT(RATOC Systems，Inc.)；ULtraSensitive^TM SP试剂盒(福州迈新生物技术开发有限公司)；CM3050S冰冻切片机(Leica公司)；DAB显色试剂盒(北京中杉金桥生物技术有限公司)；组织蛋白酶K多克隆抗体(Santa Cruz公司)；BX-43显微照相系统(Olympus公司)。

实验动物：24只雄性SD大鼠，6周龄，体质量180-220 g，由大连医科大学SPF动物实验中心提供。该实验经过大连医科大学伦理委员会批准，动物实验伦理审批号为L20180229。

1.4 实验方法

1.4.1 实验分组和造模 24只SD大鼠随机分为根尖周炎组20只及对照组4只。采用腹腔注射10%水合氯醛(1 mg/kg)对大鼠实施全麻，采取仰卧位消毒右侧下颌第一磨牙，取小号球钻开髓其近中窝，探及穿髓点后去除冠髓，直接暴露开髓孔。术后2 h禁水，术后第2天正常饲养。对照组不做任何处理。

1.4.2 MICRO-CT 模型建立4周后，取根尖周炎组及对照组各4只拍摄MICRO-CT。乙醚麻醉后处死大鼠，40 g/L多聚甲醛进行心脏灌流，分离右侧下颌骨，进行MICRO-CT扫描，扫描条件为0.060 mm/Pix像素、90 kV及110 mA，扫描厚度：SOD：97 mm，SID：37.2 mm，扫描分辨率为20 μm，导入Mimics软件使用high quality计算根尖周炎骨破坏的体积，观察模型构建情况。

1.4.3 杜仲醇提取物制备及干预甲醇15 mL加入2 g杜仲，震荡过夜，离心10 min取上清，采用三蒸水定容上清至15 mL后过滤(0.22 μm)，-20 ℃保存。在模型建立第5周，将剩余16只根尖周炎大鼠随机分为杜仲醇提取物组及生理盐水组，每组8只，杜仲醇提取物组每天灌胃杜仲醇提取物(10 mL/kg)，生理盐水组每天灌胃等量生理盐水，灌胃4周。灌胃4周后每组各取4只大鼠进行MICRO-CT扫描，分析杜仲醇提取物对根尖周骨组织的修复能力，另外取4只大鼠进行免疫组化染色观察组织蛋白酶K的表达。

1.4.4 免疫组化染色乙醚麻醉后处死大鼠，40 g/L多聚甲醛进行心脏灌流，分离右侧下颌骨，固定，EDTA常温脱钙24 d，加入20%Sucrose 4 ℃过夜，OCT低温包埋，组织平行牙长轴矢状面制备冰冻切片，37 ℃烘干2 h，PBS清洗10 min，滴加体积分数为3%H₂O₂(80%甲醇)室温1 h以灭活内源性过氧化物酶活性，滴加正常山羊血清封闭 60 min，加入组织蛋白酶K多克隆抗体(1∶250) 4 ℃过夜，加入生物素化兔抗山羊IgG 60 min，DAB显色，苏木精-伊红复染，显微镜下观察下颌第一磨牙根尖周病变区域组织蛋白酶K的表达，计数组织蛋白酶K阳性细胞数，记录每个标本的连续3张切片的均值。

1.5 主要观察指标 ①MICRO-CT扫描确认大鼠根尖周炎模型构建成功；②MICRO-CT扫描确认根尖周炎骨组织的恢复情况；③免疫组化检测根尖周炎骨破坏标志因子组织蛋白酶K的表达。

1.6 统计学分析采用SPSS 8.0 for Windows软件进行单因素方差分析，P < 0.05为差异有显著性意义。

讨论

杜仲是一种常用的中草药，其使用历史可以追溯至2000年前，杜仲提取物可以显著抑制骨质破坏、滑膜炎症和全身性炎症^[19-22]。杜仲可通过促进MC3T3-E1成骨细胞增殖与分化成熟，并上调OPG/RANKL的比值，间接抑制破骨细胞的分化和成熟，从而抑制骨吸收，可达到预防与治疗骨质疏松症的目的^[21^，^23-26]。此外，杜仲具有一定的抗炎作用，可以通过NF-κB通路进而抑制多种炎性细胞因子。杜仲可以调节Wnt信号通路进而促进成骨细胞的增殖与分化^[23-24]。根尖周炎是一类由细菌引起的口腔感染性疾病，最终导致牙槽骨的丧失，临床上针对于根尖周炎的治疗不仅仅只是治疗其细菌感染，还需要对其骨组织的愈合进行治疗^[27-29]。目前关于杜仲治疗根尖周炎骨破坏的文章尚无报道指出。与其他提取方法相比，醇提取法可以明显减少杂质，并且已有体外实验表明杜仲醇提取物与水提取物相比更具成骨功能，该实验观察杜仲醇提取物对大鼠根尖周炎组织蛋白酶K的影响。

实验通过髓腔暴露法将牙髓直接暴露在口腔环境中模拟临床根尖周炎发生发展的过程，预实验中分别在1，2，3，4，5周通过MICRO-CT确定动物模型骨破坏情况^[30-31]，结果发现在4周及5周时根尖部位出现明显的骨组织破坏，通过统计学分析显示4周及5周差异无显著性意义，因此在正式实验中选取4周作为实验组。在确定根尖周炎动物模型构建成功后，将16只大鼠根尖周炎动物模型随机分为生理盐水组及杜仲醇提取物组，每组8只。灌胃4周后每组各选取4只拍摄MICRO-CT，分析杜仲醇提取物对根尖周骨组织的修复能力。结果表明，杜仲醇提取物促进根尖周炎骨组织的恢复，差异有显著性意义(P < 0.05)；生理盐水组灌胃4周后，大鼠根尖周炎骨组织的破坏虽然有所增加，但是相对于灌胃前差异无显著性意义。组织蛋白酶K属于半胱氨酸蛋白酶家族成员，它被认为是骨破坏的标志蛋白之一^[32-38]。实验结果发现杜仲醇提取物可以抑制骨破坏标志因子组织蛋白酶K的表达，说明骨组织破坏的程度降低，进而说明杜仲醇提取物可以促进小鼠根尖周炎骨组织的愈合，其结果与MICRO-CT观察一致。

综上所述，杜仲醇提取物可以抑制根尖周炎大鼠组织蛋白酶K的表达，促进根尖周炎骨组织的愈合，但是其具体机制仍需进一步验证。由于杜仲的种类不同，并且其提取物中有效成分较多，在以后的实验中需要通过体外细胞实验鉴定其最佳有效成分，并通过分子生物学确定其促进根尖周炎骨修复的机制。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

杜仲醇提取物可促进根尖周炎模型大鼠骨组织的愈合

Alcohol extract of Eucommia ulmoides Oliv. promotes bone healing in rats with periapical periodontitis

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