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基质金属蛋白酶抑制剂的研究进展

2017-03-01贾玲玲万乾炳

华西口腔医学杂志 2017年2期
关键词:粘接剂交联剂牙本质

贾玲玲 万乾炳

口腔疾病研究国家重点实验室,国家口腔疾病临床研究中心,四川大学华西口腔医院口腔修复科,成都 610041

·综述·

基质金属蛋白酶抑制剂的研究进展

贾玲玲 万乾炳

口腔疾病研究国家重点实验室,国家口腔疾病临床研究中心,四川大学华西口腔医院口腔修复科,成都 610041

牙本质粘接混合层的长期稳定性不佳,基质金属蛋白酶等内源性酶降解胶原是导致混合层破坏的重要因素。使用酶抑制剂抑制胶原降解,维持胶原结构的完整性,是提高混合层稳定性的关键。本文重点总结了基质金属蛋白酶抑制剂(包括氯己定、乙二胺四乙酸、季铵盐类、锌离子和氧化锌、四环素类及其衍生物、异羟肟酸类抑制剂、二磷酸盐衍生物、交联剂等)的研究进展,并对未来的发展进行展望。

基质金属蛋白酶; 半胱氨酸组织蛋白酶; 牙本质; 酶抑制剂; 生物降解; 耐久性

在牙本质粘接过程中,酸蚀剂或者酸性树脂单体使牙本质脱矿,粘接剂单体渗入脱矿的胶原纤维网中,包裹胶原纤维形成混合层,这是牙本质粘接的基础[1]。由于胶原纤维网结构的复杂性,现有的粘接剂难以对胶原纤维形成完全的渗入和包裹[2-3],且树脂的水解也会导致原本被包裹的胶原暴露[4]。

基质金属蛋白酶(matrix metalloproteinases,MMPs)是一类钙、锌离子依赖的蛋白水解酶。研究表明,牙本质中含有明胶酶(MMP-2和MMP-9)[5-6]、间质溶解素1(MMP-3)[7]、釉质素(MMP-20)[8]和胶原酶-2(MMP-8)[9]等。全酸蚀和自酸蚀粘接系统都能够激活MMPs[10-11],活化的MMPs能降解暴露的胶原纤维[12-14],导致混合层完整性被破坏。Tersariol等[15]发现,牙本质中存在另一个重要的酶家族—半胱氨酸组织蛋白酶。研究[16-17]发现,龋坏牙本质中的组织蛋白酶含量明显高于正常牙本质,提示组织蛋白酶可能也参与了牙本质胶原的降解。使用酶抑制剂抑制胶原降解,维持胶原结构的完整性,是提高混合层稳定性的关键。目前,使用酶抑制剂来保护混合层的完整性是研究的热点,本文对基质金属蛋白酶抑制剂的研究进展进行综述。

1 氯己定(clorhexidine,CHX)

CHX是目前研究最多的非特异性MMPs抑制剂,能有效抑制MMP-2、-9和-8[18]。其机制可能是CHX通过螯合作用结合钙、锌离子,从而抑制MMPs催化区域的活性[19]。Scaffa等[20]研究发现,CHX对半胱氨酸组织蛋白酶也有很强的抑制作用。CHX的有效浓度为0.002%~4%[21],最常用的浓度是0.2%和2%。CHX可以单独作为一种预处理剂[22-24],但其研究结果尚存在争议。Stanislawczuk等[22]研究发现,2.0%CHX预处理能够有效减缓牙本质粘接混合层的降解。但Mobarak[23]和Lührs等[24]的研究显示,2.0%CHX预处理虽然不影响即刻粘接强度,但并不能减缓粘接强度的降低。也有研究者[25-26]尝试将CHX加入到粘接剂或处理剂中,但研究结果尚无统一的定论。Sabatini[25]将0.2%CHX加入到Peak Universal Bond的粘接剂中,发现0.2%CHX的加入不影响即刻粘接强度,且能抑制MMPs活性,但是经6个月水老化后,0.2% CHX组与对照组之间的粘接强度并无统计学差异,提示0.2%CHX不能提高粘接耐久性。Zhou等[26]将CHX加入Clearfil SE Bond的处理剂中,形成含有不同浓度CHX的处理剂,结果发现虽然0.05%CHX不能减少粘接强度的降低,但0.1%、0.5%和1.0%CHX能够有效减少粘接强度的降低。

Hebling等[27]最早发现,使用2.0%葡萄糖酸氯己定(chlorhexidine digluconate)作为一种治疗性的预处理剂能够减少粘接界面的降解。随后大量的临床研究也得出相同的结论[28-30]。但是Sartori等[31]经过3年的临床研究发现,2.0%葡萄糖酸氯己定预处理牙本质并不能提高粘接耐久性,其成功率为88%,对照组成功率为76%,二者间无统计学差异;且二者在术后敏感性、边缘变色、边缘完整性、继发龋发生率等方面也都无统计学差异。产生这种差异的原因可能与CHX和胶原的结合机制有关。CHX通过静电作用结合到胶原上[32],这种结合并不稳定,CHX逐渐被来自牙本质小管液或者唾液中的竞争性离子取代,从粘接界面溢出而失去对酶的抑制作用。基于这些特性,短期临床研究取得较好的结果,而长期研究则显示葡萄糖酸氯己定并不能提高牙本质粘接的耐久性。目前,对于CHX的临床研究绝大多数是针对全酸蚀系统,对于自酸蚀系统的研究还比较缺乏。

2 乙二胺四乙酸(ethylene diamine tetraphosphonic acid,EDTA)

EDTA是一种钙离子螯合剂,含有4个羧基基团,可与钙离子结合形成可溶性钙盐。Thompson等[33]研究发现,17%EDTA能抑制rhMMP-9和牙本质MMPs,并且呈时间依赖性。EDTA酸蚀后的牙本质,其粘接混合层抗降解能力增强[34-36],并且与乙醇湿粘接技术联合运用可获得更大的即刻粘接强度[37]。但是EDTA酸蚀作用缓慢,且与牙本质结合疏松,容易被水洗脱,故其临床适用性还有待进一步的研究。

3 季铵盐类

季铵盐类化合物是一类抗菌试剂,带正电荷。MMPs活性区域含有半胱氨酸重复序列,重复序列中的谷氨酸残基对酶的活性至关重要。谷氨酸为二元羧酸,在中性pH条件下含有一个自由羧基,并且在肽键形成后保留了一个负电荷。带正电的季铵盐通过静电作用与这些负电荷结合,阻止酶的活性区域与胶原的结合,从而抑制酶的活性[38]。甲基丙酰氧十二烷基溴吡啶(12-methacryloyloxydodecylpyrid inium bromide,MDPB)是一类可聚合的甲基丙烯酸酯季铵盐,具有抗菌性和可与树脂单体共聚的特性,已被应用到自酸蚀粘接剂Clearfil Protect Bond中[39]。体内和体外研究[40-41]都表明,使用含MDPB的粘接剂能够获得耐久性更长的粘接界面。Tezvergil-Mutluay等[38]研究发现,5.0%MDPB能够有效抑制rhMMP-9和与牙本质胶原结合的MMPs。最近研究[42]表明,MDPB还能够抑制半胱氨酸组织蛋白酶的活性。相比于其他的抑制剂,MDPB的最大优势是能够与粘接剂单体共聚,这使得MDPB不易从粘接界面中溢出,从而保持更长久的MMP抑制性[41],因而提高牙本质粘接的耐久性。苯扎氯铵(benzalkonium chloride,BAC)是具有不同长度烷基链的烷基二甲胺盐酸盐混合物,含有季铵基团,拥有广谱抗菌活性。研究[43]表明,BAC在37%磷酸中能保持稳定并且能够抑制MMPs。Sabatini等[44-45]将BAC加入粘接剂中,使其浓度分别为0.25%、0.5%、1.0%和2.0%,结果表明所有浓度都能够抑制胶原降解。最近一项研究[46]表明,在粘接剂Adper Single Bond Plus中加入0.5%和1%BAC,结果发现含0.5%BAC组粘接强度在一年内仅降低9%,而不含BAC的对照组粘接强度降低44%。甲基丙烯酸二甲氨基十二烷基酯(dimethylaminododecyl methacrylate,DMADDM)是一种新合成的季铵单体,具有抗菌活性[47]。Li等[48]研究发现,0.1%、1%、2.5%、5%、7.5%和10%DMADDM能抑制rhMMP-8和rhMMP-9,并且呈浓度依赖性,其中5%DMADDM能抑制90%的rhMMP-8和rhMMP-9,同时还能抑制牙本质弹性模量的降低(实验组降低34%,对照组降低73%)。

4 锌离子和氧化锌

MMPs是一类钙、锌离子依赖性的蛋白水解酶,微量的锌是保持MMPs活性所必需的[19]。过量浓度的锌离子能够抑制MMPs[49-50]。Souza等[50]通过酶谱法研究发现,ZnCl2能够有效抑制MMP-2和MMP-9。研究[51-53]表明,ZnCl2能够有效抑制MMPs介导的胶原降解。其作用机制可能是过量的锌与MMPs的多肽结合,改变了酶的三维空间构象,从而抑制了MMPs的活性[53]。Toledano等[54]分别将10%ZnO和2%ZnCl2加入Single Bond Plus的粘接剂中,发现二者都能够保存混合层的完整性。锌离子除了能抑制MMPs活性外,还具有诱导牙本质再矿化的能力。Osorio等[55]研究发现,锌离子能够诱导牙本质再矿化中羟磷灰石和磷钙锌矿的形成。Toledano等[56]研究表明,锌能够提高龋坏牙本质的功能性再矿化能力。Osorio等[57]研究发现,在使用Single Bond之前,用负载锌的纳米粒子的乙醇悬浮液预处理粘接界面,不会影响Single Bond的即刻粘接强度,且有利于保存粘接界面的完整性;二甲苯酚染色反应表明,负载锌的纳米粒子还有助于粘接混合层底部的功能性再矿化。利用锌对MMPs的抑制作用和诱导再矿化能力,将Zn2+或者ZnO结合到粘接剂中,可能是提高混合层稳定性的一种新方法。

5 四环素类及其衍生物

四环素及其半合成类似物强力霉素和米诺环素,以及化学修饰类四环素,是有效的MMPs抑制剂[58]。四环素类除了锌螯合作用,还能够下调MMP mRNA的表达[59],干扰蛋白的活化过程,使MMPs更容易水解[60]。Osorio等[51]和Toledano等[52]研究发现,在体外实验中,5 mg·mL-1强力霉素能抑制牙本质基质中的MMPs和rhMMP-2。Stanislawczuk等[61]研究发现,用2%米诺环素预处理37%磷酸酸蚀后的牙本质,不会影响即刻粘接强度,并且能够减少纳米渗漏。化学修饰类四环素(chemically modified tetracyclines,CMTs)是一种广谱的MMPs抑制剂。CMT-3(aka Metastat,COL-3)是抑制胶原酶作用最强的CTMs,同时也能够抑制明胶酶,能够有效减少龋坏牙本质中的基质降解[58]。关于CMT的作用机制目前尚不十分清楚,可能与其螯合作用有关。CMTs通过与酶活性位点的锌结合,能够改变酶前体分子的构象,抑制其对细胞外基质的催化活性[62]。研究者[63]用埃洛石纳米管(halloysite nanotube)负载强力霉素,并将这种复合物加入粘接剂中,成功实现了强力霉素的缓慢释放,并且能够抑制13.4%的MMP-1;但是其只研究了14 d内强力霉素的释放,更长时间的释放量以及其浓度能否起到抑制作用还有待进一步的研究。

6 异羟肟酸类抑制剂

异羟肟酸类抑制剂是一类广谱的合成类MMP抑制剂,已经被用于抗癌治疗中[64]。加拉定是一种代表性的异羟肟酸类MMP抑制剂,酶谱法已证实了加拉定对MMP-2和MMP-9的抑制性[65-66]。0.2 mmol·L-1加拉定预处理酸蚀后的牙本质,能减缓牙本质粘接强度的降低[65]。Almahdy等[66]将加拉定加入Optibond FL、Prime & Bond NT和G-Bond的处理剂中,发现含5 μmol·L-1加拉定的预处理剂能提高初始粘接强度和减少纳米渗漏。但Lührs等[24]研究发现,0.2 mmol·L-1加拉定预处理并不能抑制粘接界面的降解。巴马司他(Batimastat,aka BB94) 是另一类异羟肟酸类MMP抑制剂,其能够抑制粘接界面中的MMPs活性[66-67]。目前关于异羟肟酸类MMP抑制剂在口腔中的研究还很少,其能否应用于口腔临床中尚需进一步研究。

7 二膦酸盐衍生物

二膦酸盐是一类抗骨质疏松的药物,包括氯膦酸盐、阿仑膦酸钠、氨羟二磷酸二钠以及唑来膦酸等[68]。Heikkilä等[69]发现,二膦酸盐能抑制MMPs,其机制可能是通过螯合锌离子和钙离子。聚乙烯基磷酸(polyvinylphosphonic acid,PVPA)中含有–C–P膦酸酯键,与二膦酸盐中的–C–O–P 酯键具有结构相似性[70]。Tezvergil-Mutluay等[70]研究发现, PVPA能抑制rhMMP-9。与CHX类似,PVPA能通过静电作用与胶原结合。但不同的是,PVPA能通过乙基二甲胺丙基碳化二亚胺[1-ethyl-3- (3-dimethylaminopropyl)carbodiimide,EDC]交联到胶原基质上。PVPA不仅能够抑制MMPs,还能诱导牙本质再矿化,作为牙本质基质蛋白(dentin matrix protein,DMP)的模板类似物,诱导无定形钙磷纳米颗粒进入胶原基质中,促进牙本质再矿化[71-72]。这些研究结果提示,PVPA或许能够在抑制MMPs的同时,诱导牙本质再矿化,从而提高牙本质粘接的耐久性。在牙本质粘接领域,目前关于PVPA的研究仍然较少,其能否抑制牙本质粘接界面的降解还有待更多的研究。

8 交联剂

常见的交联剂分为化学交联剂、天然交联剂和物理交联剂三类[73]。

8.1 化学交联剂

戊二醛能减缓胶原降解的速率,提高牙本质胶原的性能。研究[74]表明,5.0%戊二醛处理酸蚀后的牙本质1 min,能增加牙本质的弹性模量。近几年,EDC因其性质稳定、毒性低而受到了越来越多的关注。研究[75]发现,0.1、0.3和0.5 mol·L-1EDC预处理酸蚀后的牙本质,不会对成牙本质样细胞产生毒性。Tezvergil-Mutluay等[76]研究表明,0.3 mol·L-1EDC作用1 min即可抑制rhMMP-9的活性。Mazzoni等[77]用原位酶谱法证实,0.3 mol·L-1EDC能够抑制MMP-2和MMP-9。Scheffel等[74,78]研究也表明,EDC能够提高胶原强度,增强粘接界面稳定性,延长粘接耐久性。丙酮作为溶剂能够提高EDC的交联能力,增强EDC抑制胶原降解的能力[79]。

8.2 天然交联剂

天然交联剂具有低毒性和可持续的特点,是近几年研究的热点。常见的天然交联剂有京尼平、多酚类和原花青素(proanthocyanidins,PACs)等[73]。PACs是一种凝缩单宁类物质,无毒性,是有效的胶原酶抑制剂[80]。Epasinghe等[81]研究发现,1.0%PACs能抑制超过90%的rhMMP-2、-8、-9以及75%~90%的半胱氨酸组织蛋白酶,其抑制作用明显高于CHX。PACs作用非常迅速,3.75%PACs预处理37%磷酸酸蚀后的牙本质10 s,即可提高胶原抗水解能力,且其交联牙本质胶原的能力强于戊二醛[82-83]。近几年,研究者[84-86]尝试将PACs加入粘接剂中。Epasinghe等[84]研究表明,将浓度低于2%的PACs加入粘接剂中,不会影响即刻粘接强度,但树脂聚合度降低。其原因可能是PACs是游离基清除剂[87],会干扰粘接剂单体的聚合。基于上述研究结果,用PACs作为处理剂可能是保护混合层完整性的一种新方法,且由于PACs交联作用迅速,该方法具有一定的临床可行性。

8.3 物理交联剂

核黄素(riboflavin)是一种物理交联剂,在紫外光照射下能够产生氧自由基,氧自由基能够使甘氨酸的氨基与相邻链羟脯氨酸和脯氨酸的羰基形成共价键,产生交联作用。目前,核黄素和紫外线A(ultra violet A,UVA)联合应用已成为治疗眼科疾病(如角膜病)的一新方法。在牙本质粘接方面,核黄素作为交联剂的研究取得了较好的结果[88-90]。Cova等[88]研究表明,核黄素/UVA能够抑制牙本质MMPs(特别是MMP-9),且能够提高即刻粘接强度和粘接界面稳定性。Fawzy等[89-90]研究发现,核黄素/UVA能够增强牙本质胶原的机械性能和抵抗水解的能力。核黄素具有良好的生物相容性和操作简便性。虽然在实验室中证明核黄素/UVA有效[90],但关于使用UVA的安全性和在牙科中的实用性还有待进一步的研究。

9 其他外源性抑制剂

其他外源性抑制剂如二甲基亚砜[91]、特异性抑制剂SB-3CT[92]和金纳米粒子[93]等也有报道,但是这些抑制剂能否应用于口腔临床还有待更加系统的研究。

综上所述,利用酶外源性抑制剂抑制胶原降解,是提高混合层稳定性的一种具有较好研究前景的方法。虽然CHX、MDPB等已应用于临床,但是其远期效果仍不佳。利用锌离子和PVPA等抑制MMPs,同时诱导牙本质再矿化,可能是一种保护混合层完整性的新思路。交联剂除了能够抑制MMPs外,还能够交联胶原纤维,提高胶原的机械性能和抵抗水解的性能,可能是未来外源性抑制剂研究的重点领域。由于单一种类抑制剂的作用有限,多种抑制剂联合应用可能是未来研究的趋势。

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(本文编辑 李彩)

Progress on matrix metalloproteinase inhibitors

Jia Lingling, Wan Qianbing. (State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Dept. of Prosthetics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China)

Continuing advances in dentin bonding technology and adhesives revolutionized bonding of resin-based composite restorations. However, hybrid layers created by contemporary dentin adhesives present imperfect durability, and degradation of collagen matrix by endogenous enzymes is a significant factor causing destruction of hybrid layers. Bond durability can be improved by using enzyme inhibitors to prevent collagen degradation and to preserve integrity of collagen matrix. This review summarizes progress on matrix metalloproteinase inhibitors (including chlorhexidine, ethylenediaminetetraacetic acid, quaternary ammonium salt, tetracycline and its derivatives, hydroxamic acid inhibitors, bisphosphonate derivative, and cross-linking agents) and suggests prospects for these compounds.

matrix metalloproteinase; cysteine cathepsins; dentin; enzyme inhibitors; biodegradation; durability

R 783.2

A

10.7518/hxkq.2017.02.019

2016-08-11;

2016-12-09

贾玲玲,硕士,E-mail:jlingling0612@126.com

万乾炳,教授,博士,E-mail:champion@scu.edu.cn

Correspondence: Wan Qianbing, E-mail: champion@scu.edu.cn.

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