Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (32): 5162-5170.doi: 10.12307/2021.219
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Fan Chongshan1, Sun Mingshuai1, Han Wenchao1, 2
Received:
2020-10-16
Revised:
2020-10-20
Accepted:
2020-11-09
Online:
2021-11-18
Published:
2021-07-26
Contact:
Han Wenchao, Master’s supervisor, Chief physician, Henan University of Chinese Medicine, Zhengzhou 451200, Henan Province, China; Affiliated Hospital of Henan University of Chinese Medicine (Puyang Hospital of Traditional Chinese Medicine), Puyang 457000, Henan Province, China
About author:
Fan Chongshan, Master candidate, Physician, Henan University of Chinese Medicine, Zhengzhou 451200, Henan Province, China
CLC Number:
Fan Chongshan, Sun Mingshuai, Han Wenchao. Proinflammatory factors and matrix metalloproteinases: status and roles in the pathogenesis of osteoarthritis[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(32): 5162-5170.
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2.1 骨关节炎发病原因 2.1.1 感染、损伤或手术 多种细菌和病毒感染骨关节后,会导致某些类型骨关节炎的发展,软骨撕裂、关节脱臼、韧带损伤以及关节畸形者发生骨关节炎的风险更高。2017年的一项回顾性队列研究显示,发生前交叉韧带撕裂和外侧半月板损伤者在10年内发生骨关节炎的风险提升1.5倍[4];滑膜炎也与手部骨关节炎影像学进展有关[5]。关节中软骨细胞失去基质保护和营养后会发生退变和死亡[6],浅表的软骨损伤后24 h内,其周围软骨细胞的分裂、基质合成、分解代谢酶活性均明显。关节内组织和机械力学应力之间的复杂相互作用导致半月板挤压,其可能参与骨关节炎的发生发展。 2.1.2 肥胖或超重 肥胖一直被认为是引发膝关节炎的危险因素之一,超重和肥胖患者罹患骨关节炎的风险更大,同时其也会恶化骨关节炎的进程。关节是人体负重部位,当体质量增加后,其负荷随之增加,因而加大发生关节损伤的可能。有荟萃分析显示,肥胖或超重者发生膝骨关节炎的风险是正常体质量者的2.96倍,且体质量指数越高,膝关节炎的风险越大[6],因而控制体质量是预防骨关节炎的重要措施。妇女在10年内减重≥5 kg,可能降低50%发生膝骨关节炎的风险[7];维持越长时间的高体质量指数,发生膝骨关节炎的风险也越高[8]。高脂血症也是新发手部骨关节炎的独立危险因素[9]。罗美杰等[10]的一项整群抽样调查结果显示,膝关节炎患者的体质量指数越大,其西安大略和麦克马斯特大学骨关节炎指数越高,且患者发生跌倒的风险也越高。 2.1.3 慢性劳损 骨性关节炎更多见于慢性损伤,尤其是长期的劳损,包括长期行走或者端坐姿势不正确,以及过度负重。在从事各种体育项目的运动员中膝骨关节炎的发病率可达16%-95%[11],主要是由于运动员长时间的运动训练和高强度的训练负荷使膝关节受到反复冲击,引起关节软骨负荷改变及损伤,导致骨赘形成,增加远期骨性关节炎的发病风险。 2.1.4 先天性骨骼和软组织畸形 骨性关节炎与患者先天性骨骼和软组织畸形导致的关节不稳也有很大关联,例如髋关节发育不良患者先天髋关节解剖结构异常,在生长发育过程中髋臼对股骨头的覆盖逐渐减少,髋臼和股骨头的匹配度下降,造成髋关节生物力学长期异常,最终将发展成为髋关节骨关节炎[12]。研究发现某些骨关节炎患者肢体外观虽正常,但存在肢体扭转畸形,于是提出了扭转畸形与骨关节炎关系的新课题,人们发现膝内翻、膝外翻、足外翻、足内翻等患者成年后常有膝、髋的骨关节炎存在[13]。 2.1.5 基因 骨关节炎被认为是一种多基因疾病,有研究认为基因对骨关节炎的影响超过65%。WARNER等[14]的全基因组关联分析研究已确定了21种独立的骨关节炎易感基因位点。ALDH1A2基因rs4238326多态性可能与非创伤性膝骨关节炎易感性有关[15];TACR1基因多态性rs11688000与有症状骨关节炎的风险降低有关[16];COMT基因多态性Val158Met与髋骨关节炎相关的疼痛有关[17]。LI等[18]发现骨关节炎小鼠脊髓前角细胞中miRNA-146a与步态平衡能力相关。早发性严重性骨关节炎的发生与Ⅱ型胶原前蛋白突变有关[19]。 2.1.6 其他 女性比男性更容易发生骨关节炎,尤其在50岁以后。在男性和女性的组织发育过程中以及整个生命周期中,膝盖组织都受到性激素的调节,尽管绝经与女性骨关节炎严重程度增加有关,但仅全身性雌激素不能解释观察到的性别差异。除了膝骨关节炎的患病率增加之外,女性通常比男性更痛苦,且对其功能和生活质量的影响更大[20],雌激素替代疗法可显著减少髋骨关节炎以及膝骨关节炎的发生[21]。软骨组织成分暴露后可引发自身免疫反应,从而增加蛋白降解及炎症,造成软骨进一步损伤,进而使更多的软骨组织暴露于免疫系统中,形成恶性级联反应[22-25]。 2.2 促炎症细胞因子在骨关节炎发病中的作用 承受高机械负荷的正常关节中软骨细胞的凋亡和增殖以及细胞外基质降解和合成均处于动态平衡中,其中白细胞介素1、白细胞介素6、白细胞介素17、C-反应蛋白、肿瘤坏死因子α等多种细胞因子参与这种动态平衡。大量研究认为这些因子均可参与骨关节炎的发展,发生炎症反应的软骨细胞会产生MMP,从而引起软骨降解,进而使骨关节炎进展。 2.2.1 白细胞介素1 白细胞介素1是分子质量为17 kD的细胞因子,可由巨噬细胞、软骨细胞、滑膜细胞、单核巨噬细胞等多种细胞产生,有白细胞介素1α和白细胞介素1β两种亚型,二者有25%同源性,以前体形式分泌出来,在白细胞介素转换酶作用下,转换成活性白细胞介素1。软骨细胞膜上分布有可结合白细胞介素1的受体,高水平的白细胞介素1与软骨细胞膜上受体结合,通过信息传递系统,将改变的信息输送到细胞内,从而干扰了软骨细胞的正常代谢活性,如抑制软骨细胞表型的分化[26]、诱导软骨细胞凋亡[27]、抑制软骨细胞增殖[28];白细胞介素1还可诱导MMP表达并促使其活化,引起软骨基质降解[29];白细胞介素1对滑膜的影响可刺激滑膜细胞释放中性蛋白酶和前列腺素E2,引起滑膜炎症和促进骨吸收[30]。许多研究在动物模型和体外培养方面实验证实白细胞介素1在骨关节炎的发病进程中起着关键作用。研究证实动物关节腔内注射重组的白细胞介素1可以成功诱发膝骨关节炎,再现白细胞介素1对关节软骨的破坏作用[31]。LANDSBERG等[32]将骨关节炎患者膝关节软骨细胞及滑膜细胞进行体外培养,其合成的白细胞介素1α和白细胞介素1β水平均升高。郑剑平等[33]的研究表明,膝骨关节炎患者关节液及血清中存在大量白细胞介素1,显著高于正常对照组,且膝骨关节炎患者的病程越长,症状越重,关节滑液中白细胞介素1含量增多就越显著。但是VAN DALEN等[34]研究认为,白细胞介素1α和白细胞介素1β不参与胶原酶诱导骨关节炎的滑膜炎症和软骨破坏,提示其他介质参与了关节损伤。因此,有关白细胞介素1对关节破坏的确切作用机制还需深入研究。 2.2.2 白细胞介素6 白细胞介素6于20世纪80年代被克隆出来,首次被证明能促进T淋巴细胞和B淋巴细胞的活化,并调节炎症相关的急性期反应。白细胞介素6是一种加速关节降解和骨关节炎进程的关键炎症因子,白细胞介素6升高可用于预测骨关节炎。骨关节炎患者的外周血中存在高水平的白细胞介素6和其他细胞因子,并且在骨关节炎动物模型中也可以检测到高水平的白细胞介素6[35]。一项前瞻性研究显示,如果个体的体质量指数较高,并且循环血清中白细胞介素6水平增加,则更容易被诊断为膝骨关节炎[36]。白细胞介素6也被证明是低氧诱导因子2α诱导的实验性骨关节炎小鼠中MMP-13 表达的关键介质[37],并影响软骨基质的合成代谢过程[38]。白细胞介素6可增加骨关节炎的严重程度,抑制白细胞介素6/Stat3信号可减缓实验性骨关节炎的进展[39-40]。MOKTAR等[41]观察膝骨关节炎患者关节软骨中白细胞介素6 mRNA水平,并与同一患者的正常软骨进行比较,21例患者中有12例软骨中白细胞介素6 mRNA表达上调,其余白细胞介素 6 mRNA表达下调。统计分析显示,骨关节炎患者的白细胞介素6 mRNA水平与正常软骨相比差异无显著性意义(P > 0.05)。膝关节软骨中白细胞介素6 mRNA水平出现个体间差异的原因可能是,白细胞介素6作为一种分解代谢因子,其表达可能受到其他细胞因子的影响。白细胞介素6在骨关节炎中的表达调控尚不完全清楚,这些结果将刺激更多的关于白细胞介素6作为潜在治疗靶点的研究。 2.2.3 白细胞介素17 白细胞介素17是近年发现的一种主要由CD4+辅助性T细胞17(Th17)合成及分泌的细胞因子家族,通过与细胞表面相应受体结合而发挥对机体的调控作用。白细胞介素17能刺激组织、细胞合成并释放中性粒细胞趋化因子、炎性细胞因子、MMP及破骨细胞分化因子等诱导局部组织炎症反应。WANG等[42]评价白细胞介素17对兔膝关节的影响,将实验兔右膝作为对照组,左膝随机分为4组,即Hulth组和3个白细胞介素17组(1,10,50 ng组);术后12周时,采用X射线片分析、组织学评价和聚合酶链反应分析软骨退变相关标志物的mRNA表达水平。与Hulth组一样,10 ng和50 ng白细胞介素17组表现出典型的骨关节炎表现,与Hulth法诱导的骨关节炎相似。NA等[43]的研究表明,白细胞介素17通过调节骨关节炎小鼠模型中的几种炎症递质加速软骨和小肠的破坏,在骨关节炎的发生发展中起着重要作用。BAI等[44]采用聚合酶链反应-限制性片段长度多态性分析方法,对594例膝骨关节炎患者和576例健康对照者白细胞介素17A rs2275913和白细胞介素17F rs763780进行多态性检测,结果表明白细胞介素17基因多态性可能与膝骨关节炎的高危发生有关。SNELLING等[45]的临床研究显示晚期膝、髋关节骨关节炎患者滑液中白细胞介素17水平明显升高,骨关节炎患者血清和滑液中的白细胞介素17水平与影像学图像病变严重程度也呈正相关,以白细胞介素17为基础对患者进行分层,可以确定那些对靶向治疗反应灵敏的患者。另外,白细胞介素17可抑制软骨细胞合成蛋白聚糖,并促进细胞基质蛋白酶的产生[46]。白细胞介素17在骨关节炎疾病发生和发展中所起的作用已基本肯定,但其作用途径以及其与症状的关系尚未完全明确,从分子水平阐明骨关节炎的发病途径以及针对该途径的免疫治疗都有待于进一步探索。 2.2.4 C-反应蛋白 骨关节炎患者血清C-反应蛋白水平升高,除了提示全身炎症外,C-反应蛋白本身也可能在骨关节炎的发生发展中起作用。KOZIJN等[47]在人类C-反应蛋白转基因小鼠模型中评估了C-反应蛋白本身是否参与了代谢性骨关节炎的发展,结果显示,在高脂饲料诱导的代谢功能障碍背景下,C-反应蛋白高表达通过增加了软骨退变和骨赘生而加重骨关节炎。CONROZIER等[48]研究数据表明,快速破坏性髋关节骨性关节炎可能与一定程度的炎症有关,这些炎症反应可通过血清C-反应蛋白水平的显著性增加来反映。ZHANG[49]的研究显示,血清C-反应蛋白水平与膝关节炎的发生相关,C-反应蛋白浓度增高的患者可能有发生膝关节炎的可能性。然而,C-反应蛋白水平升高与膝关节炎进展无关;此外,膝关节炎患者疼痛程度越高,C-反应蛋白浓度越高。高敏C-反应蛋白是急性时相反应的一种下游介质,具有免疫调节功能,目前的高敏C-反应蛋白试剂盒可检测出更低浓度的C-反应蛋白,能为临床应用提供更多有价值的参考信息,可以预测骨关节炎病变发生、发展和预后[50-51]。上述这些发现提示选择性地针对C-反应蛋白活性的干预措施可以改善代谢性骨关节炎的发展。 2.2.5 肿瘤坏死因子α 肿瘤坏死因子α是一种促炎性细胞因子,在骨关节炎的发病机制中起重要作用[52]。CHEN等[53]进行的一项研究证明,白细胞介素1β和肿瘤坏死因子α增加了关节软骨僵硬和收缩功能受损的风险。血清白细胞介素6和肿瘤坏死因子α水平与老年人膝关节骨关节炎相关[54];在体外,促炎性因子白细胞介素1β和/或肿瘤坏死因子α上调软骨细胞亚群中MMP-1,3 mRNA,促使骨关节炎发病[55]。有研究表明,膝骨关节炎患者肿瘤坏死因子α mRNA表达量是健康对照组的1.56倍;肿瘤坏死因子α水平与骨关节炎分级一致,MMP-13水平升高与西安大略和麦克马斯特大学骨关节炎指数有显著相关性[56]。基于这些观察结果,肿瘤坏死因子α可能为骨关节炎的病因研究提供线索。肿瘤坏死因子α能促进Ⅱ型胶原和蛋白多糖的分解代谢,从而损害软骨细胞外基质的完整性和组织稳态。一些研究表明,肿瘤坏死因子α诱导软骨细胞死亡,并阻碍软骨祖细胞的迁移[57-58],种族分层分析显示亚洲人对肿瘤坏死因子αrs1800629易感,增加了患骨关节炎的风险[59]。 2.3 MMP在骨关节炎发病中的作用 MMP是水解细胞外基质的一种蛋白水解酶,被认为是机体生理重建和病理破坏的主要基础因素之一,在软骨基质大分子细胞分裂中起重要作用,破坏关节软骨细胞外基质结构和功能的完整性。MMP是酶活性依赖锌离子的蛋白酶超家族[60],根据其结构域结构、序列相似性和底物的特异性,可分为胶原酶、基质溶解素和明胶酶等亚家族。此文主要介绍与骨关节炎关系密切的几种常见的MMP。 2.3.1 MMP-1 MMP-1是成纤维细胞型胶原酶,基因位于11号染色体(11q22.3)长臂上,在软骨细胞、成纤维细胞、上皮细胞、内皮细胞、肿瘤细胞等细胞中表达[61]。病理条件下,MMP-1表达水平明显升高,降解细胞外基质胶原蛋白并介导软骨破坏[62-64]。MMP-1在骨关节炎软骨细胞中的表达高于正常软骨细胞,提示MMP-1在骨关节炎发病机制中起主导作用[65]。Ⅱ型胶原是关节软骨细胞外基质的一个重要成分,能够为关节软骨提供张力强度,并维持蛋白多糖和水分所形成的膨胀压。大量实验表明,约60%的骨关节炎患者关节液中会产生碱性磷酸钙结晶,这些结晶可以刺激关节软骨和滑膜组织中MMP-1的合成,进而破坏细胞外基质的动态平衡[66]。为探讨MMP-1表达量与骨关节炎软骨降解程度的关系,WU等[67]观察兔前交叉韧带横断模型骨关节炎进展过程中MMP-1在软骨和滑膜中的水平和分布,结果显示,MMP-1参与了兔前交叉韧带横断模型骨关节炎的形成,其表达量与软骨降解程度有关,滑膜MMP-1表达的增加滞后于软骨,提示骨关节炎的病理来源于软骨,但滑膜炎也可能参与软骨的降解,尤其是骨关节炎的中晚期。HWANG等[68]的临床研究表明,骨关节炎患者早期滑液中MMP-1浓度较高,且随着骨关节炎的发展而降低。以上研究显示,MMP-1降解关节软骨细胞外基质,造成软骨的病理性破坏,进而引起骨关节炎的发生。 2.3.2 MMP-13 MMP-13是导致软骨退行性改变的关键酶,被认为是骨关节炎发病过程中发生退行性改变的主要因素。由于MMP-13在骨关节炎患者的关节和关节软骨中明显过度表达,而在正常成人组织中几乎无法检测到,因此备受关注。众所周知,MMP-13在骨关节炎关节中起着细胞外基质降解酶的作用[69-70]。在实验性小鼠骨关节炎模型中,MMP-13水平与骨关节炎早期发生软骨细胞肥大分化有关[71],其过度表达可通过过度细胞外基质降解诱导骨关节炎的发生[72]。在临床样本中,MMP-13在骨关节炎过程的不同阶段异常表达,在骨关节炎早期软骨中MMP-13表达上调,在骨关节炎晚期MMP-13表达下调[73]。祁雷[74]采用膝关节内侧副韧带离断+内侧半月板切除的方法建立动物骨关节炎模型,MMP-13和ADAMTS-5在骨关节炎发病过程中的不同时期表达水平有明显变化,可作为骨关节炎防治研究的评价指标。李跃军等[75]研究认为MMP-13和β-catenin在骨关节炎组滑膜组织中均表现为高表达状态,两者在骨关节炎与非骨关节炎组表达差异有显著性意义,MMP-13与β-catenin在参与骨关节炎软骨退变和滑膜炎症反应等病理变化过程中密切相关。因此,MMP-13是软骨降解网络中的一个中心节点[76],因此有必要了解MMP-13在骨关节炎发病中的作用。 2.3.3 其他 MMP-2参与细胞外基质降解,它能够降解Ⅰ,Ⅳ,Ⅴ、Ⅶ,Ⅹ型胶原、层粘连蛋白、弹性蛋白、纤维连接蛋白和蛋白多糖[77],研究表明,不同原因导致的骨关节炎表现为关节滑膜细胞MMP-2的分泌量和活性增高[78]。MMP-9又称为明胶酶B,从人类巨噬细胞中纯化而来,许伟朋[79]的研究表明肿瘤坏死因子α、前列腺素E2和MMP-9在轻度骨关节炎组滑膜中的表达较正常组明显增多,重度骨关节炎组较轻度骨关节炎组明显增多,与骨关节炎患者的病程长短、病情严重程度呈正相关性。肿瘤坏死因子α及前列腺素E2均能上调MMP-9的表达,致使MMPs/基质金属蛋白酶抑制剂1比例失衡,引起软骨基质的破坏,参与骨关节炎发病及渐进性加重。MMP-3又称为基质溶解酶1,由滑膜内皮细胞产生,可通过降解细胞外多糖直接作用于软骨基质。CHU等[80]研究发现骨关节炎实验兔血清和关节液中MMP-3水平明显增高,可有效判断膝骨关节炎的严重程度。 2.4 针对炎症因子的骨关节炎非手术治疗进展 2.4.1 口服药物治疗 国际骨关节炎学会制定的《膝关节骨关节炎非手术治疗指南》推荐用非固醇抗炎药(尤其是特异性的环氧化酶2抑制剂)控制病情,“指南”还推荐了生物制剂、软骨保护剂及细胞移植等新技术[81],但生物制剂、细胞移植因其治疗费用及各级医院医疗水平限制在临床并不普及。非类固醇抗炎药有双氯芬酸钠、塞来昔布及美洛昔康等,它们能够通过阻断一些特殊的合成路径,减少关节内的炎症因子含量,以及促进软骨基质蛋白聚糖合成,从而很好地缓解骨关节炎患者的关节疼痛。双氯芬酸钠目前主要有2种给药途径,口服和局部给药已被确立为标准治疗方法之一。一般来说,口服非类固醇抗炎药的耐受性良好;然而,一项叙述性综述表明,局部给药比口服双氯芬酸钠具有更好的耐受性,不良反应较小,特别是口服给药后有胃肠道出血的副反应[82]。此外,对于一些有潜在风险和不良反应史的患者,局部给药被认为是治疗肌肉骨骼疼痛的合理选择[83]。一项荟萃分析显示塞来昔布治疗(每天口服200 mg)可显著改善骨关节炎的疼痛和功能。然而,与安慰剂对照组相比,塞来昔布在10-13周治疗后会发生更严重的胃肠道不良反应,尤其是腹痛[84]。动物模型证实10 mg/kg的美洛昔康是降低骨关节炎大鼠肿瘤坏死因子α水平的潜在剂量,其对动物疼痛的抑制可能与肿瘤坏死因子α水平降低有关[85]。Hussain等[86]评估白藜芦醇作为美洛昔康的佐剂对90 d内疼痛和功能活动的影响,并监测肝肾功能、血脂和血液学指标。临床和生化指标表明,500 mg/d的白藜芦醇作为美洛昔康的佐剂,对膝骨关节炎患者而言安全和耐受性良好,在治疗膝骨关节炎疼痛和改善身体功能方面优于美洛昔康。 此外,一系列新的骨关节炎治疗药物,如双醋瑞因、多西环素等,都是针对不同炎症因子、MMP的治疗药物[87-88]。但应该认识到,这些抗炎症因子药物的不良反应始终困扰着骨关节炎患者的治疗,可根据情况适当加用胃肠黏膜保护剂、质子泵抑制剂等保护胃肠,建议长期服用患者定期复查肝肾功能。以硫酸氨基葡萄糖为代表的氨基葡萄糖类药物,不仅能发挥软骨修复作用,还有一定的炎症因子抑制作用[89-90]。如动物口服硫酸氨基葡萄糖后,关节滑液中的肿瘤坏死因子α和白细胞介素1β便会显著下降,又如氨基葡萄糖联合其他药物可以使多种炎症因子的含量显著下降,关节功能得以明显改善[91-92]。与此同时,该药较少的不良反应反映了临床治疗的安全性。 2.4.2 关节腔内给药 关节腔内注射使用药物有透明质酸、糖皮质激素及自体富血小板血浆等。陈波等[93]采用透明质酸钠注射治疗膝骨关节炎患者,治疗4周后,膝骨关节炎严重性指数评分明显降低,白细胞介素1β水平也明显低于对照组,可见透明质酸钠在改善老年膝骨关节炎患者病情、减轻炎性递质水平方面可发挥积极作用。关节腔内直接注射糖皮质激素的目的也是为了抑制炎症因子的产生[94],而且这种治疗方法联合非类固醇抗炎药更加直接、疗效更加突出。杨彦飞等[95]研究显示,对轻度或X射线片退变Ⅰ,Ⅱ级膝骨关节炎患者,关节腔注射透明质酸钠或透明质酸钠+复方倍他米松注射液均有效,注射透明质酸钠+复方倍他米松注射液效果优于单独注射透明质酸钠;对于中度患者,单独注射透明质酸钠无效,透明质酸钠+复方倍他米松注射液注射有效;对于重度或X射线片退变Ⅲ,Ⅳ级患者,单独注射透明质酸钠或透明质酸钠+复方倍他米松注射液注射均无效。但是临床应用糖皮质激素有许多不良反应,其不仅可以缓解症状,而且也能加重软骨磨损,主要是激素不利于钙和磷的吸收,以及降低疼痛敏感性[96]。富血小板血浆是患者自身全血离心分离出的富含多种生长因子的血小板浓缩物,多用于膝骨关节炎早期治疗。曾佳森等[97]研究显示膝关节腔内注射自体富血小板血浆与透明质酸钠,近期效果类似,治疗6,12个月后临床效果优于透明质酸钠,能有效改善患者的疼痛,控制病情的迁延,降低分解性细胞因子(白细胞介素1β、白细胞介素6、MMP-9、MMP-13、肿瘤坏死因子α)表达水平。 2.4.3 中医治疗 由于中医药疗法疗效可靠、不良反应少等优势,在国内的临床实践中占有一席之地。中药复方制剂以及单方和有效成分均能通过调节相关细胞因子、生物活性分子、蛋白酶表达及血液循环等因素改善关节炎症状,影响软骨细胞代谢,防止或延缓关节软骨退变。同样针灸和推拿等疗法也能通过影响局部关节代谢,改善软骨损伤,减轻关节疼痛,对骨关节炎发挥治疗作用。夏璇等[98]研究表明痹祺胶囊可以更好地改善膝骨关节炎患者的关节僵硬和功能状态,可以更好地改善未合并服用止痛药患者的膝关节影像学结果。槲皮素是一种存在于多种植物的五羟基黄酮类化合物,研究发现槲皮素可减轻关节软骨损伤,缓解关节肿胀,抑制血清中MMP-9、MMP-13和白细胞介素1β的表达,在骨关节炎动物模型中起到保护关节软骨的作用[99]。KANZAKI等[100]将40例有症状的膝骨性关节炎患者随机分为2组,分别给予膳食补充剂(每天1 200 mg氨基葡萄糖、60 mg硫酸软骨素和 45 mg槲皮素苷)或安慰剂,治疗和随访持续16周,结果显示膳食补充剂在减轻膝骨关节炎相关临床症状方面比安慰剂更有效。此外,软骨代谢生物标志物分析显示,在随访期间,膳食组的Ⅱ型胶原合成/降解平衡有改善的趋势。在一项随机、开放、平行、对照的临床研究中,139例膝骨关节炎患者被随机分配2组,接受500 mg姜黄素胶囊3次/d,或50 mg双氯芬酸片2次/d,共28 d[101];在第14,28天,姜黄素治疗组的疼痛严重程度和膝关节损伤和骨关节炎评分与双氯芬酸组相似,差异无显著性意义;在第7天,与双氯芬酸相比,服用姜黄素患者的肠胃气胀发作次数明显减少(P < 0.01);第28天,姜黄素具有减肥作用和抗溃疡作用(P < 0.01);姜黄素组患者均不需要H2阻断剂,双氯芬酸组有19例需要H2阻断剂(P < 0.01);姜黄素组的不良反应明显较少,姜黄素在膝骨关节炎患者中表现出更好的耐受性,结果可见姜黄素可作为膝骨关节炎患者非类固醇抗炎药不良反应的替代治疗方案。另外一项为期12周的多中心、随机、双盲、安慰剂对照、平行的研究方案,旨在评估杜仲提取物对轻度骨关节炎患者的疗效和安全性;将招募100例轻度骨关节炎患者按1∶1的比例随机分为2组,一组接受杜仲提取物12周,另一组接受安慰剂12周,通过目测类比评分、西安大略和麦克马斯特大学骨关节炎指数、健康状况调查简表和实验室测试结果进行评估,这项临床试验有望为杜仲提取物治疗轻度骨关节炎的有效性和安全性提供证据[102]。HU等[103]研究表明,中药复方杜仲补骨颗粒能有效提高美洛昔康的疗效,且杜仲与美洛昔康联合用药优于单用美洛昔康。韩国学者PARK等[104]探讨了三七、地黄、刺五加的水溶性提取物治疗膝骨关节炎6周的安全性和有效性,结果显示其能有效改善疼痛和关节功能。 针灸能够有效减轻骨关节炎患者的疼痛,并改善其关节功能。有基础及临床研究对于针灸在骨关节炎中的机制进行探索,认为针灸可能通过刺激相关炎性因子通路,调节细胞因子水平,改善骨关节炎的炎症反应,从而发挥治疗作用[105]。在兔关节软骨中的研究也证实,温针灸通过抑制软骨细胞凋亡,减少细胞中尿激酶型纤溶酶原激活物生成,进而阻断MMP的活化,保护骨关节炎中的关节软骨[106],同样温针灸减轻膝骨关节炎大鼠的炎性损伤可能基于减少软骨组织中ROCK、p-LIMK1和p-Cofilin的表达[107],以及降低滑膜组织中肿瘤坏死因子α表达,并抑制软骨中Wnt3a和β-catenin蛋白表达[108]。基于90例膝骨关节炎患者的随机对照研究也证实,经外奇穴温针灸是通过降低关节液肿瘤坏死因子α、白细胞介素1和一氧化氮水平来改善患者关节软骨损伤[109]。汪国翔等[110]将72例膝骨关节炎患者随机分为滞动针法组和药物组(n=36),滞动针法组以犊鼻、内膝眼、足三里、阳陵泉、阴陵泉、血海、梁丘、鹤顶为主要穴位,施以滞动针法,留针30 min,1次/d;药物组口服塞来昔布胶囊,200 mg/次,1次/d;两组均以14 d为1个疗程,每个疗程间休息2 d,连续治疗2个疗程;结果显示,滞动针法可有效缓解膝骨关节炎患者疼痛症状、改善关节功能,作用和口服塞来昔布胶囊相当。因此说明针灸治疗骨关节炎也是通过调节多种细胞因子、减轻关节软骨损伤从而达到治疗的目的。推拿具有行气止痛、活血通络、荣润关节、舒筋活络等功效,可改善膝骨关节炎患者膝关节疼痛、僵硬、活动受限以及异常步态等临床症状。此外,CHEN等[111]研究发现艾灸和针刺治疗均能减轻膝骨关节炎的症状,且艾灸疗效优于针刺,其作用机制可能与降低患者血清炎性因子和氧化应激因子水平有关。动物研究发现,推拿还能通过提高膝骨关节炎关节液中氧自由基的清除能力,改善关节软骨形态与功能,发挥对骨关节炎的防治作用[112]。 2.4.4 物理疗法 物理疗法适用于骨关节炎的慢性期,对亚急性期疼痛有较好的缓解作用,还能增加局部血液循环,减轻滑膜炎症,使软骨得到充分的营养,延缓软骨的退行性变。物理治疗是早期无严重增生、关节畸形患者的有效治疗方法。DEYLE等[113]的研究表明,手法物理治疗和监督性运动相结合可改善膝关节骨关节炎患者的功能,并可能延迟或避免手术干预的需要。ZHONG等[114]观察小剂量体外冲击波疗法对Kellgren Lawrence Ⅱ级或Ⅲ级骨关节炎患者膝关节疼痛、下肢功能及软骨改变的疗效,结果显示,4周小剂量体外冲击波疗法治疗轻中度膝关节骨性关节炎患者的疼痛缓解和功能改善优于安慰剂,但对关节软骨有一定的负面影响。 2.4.5 再生医学疗法 在过去的30年里,软骨组织工程已经从治疗关节软骨的局部病变发展到针对骨关节炎的治疗策略,细胞疗法对于关节软骨损伤的修复具有重要意义。间充质干细胞具有自我更新和定向分化的潜能,能够修复软骨组织,抑制软骨细胞分泌炎性因子,还可以在体内定向分化成软骨细胞,这为间充质干细胞治疗骨关节炎提供了理论依据。基于间充质干细胞的细胞疗法为骨关节炎的治疗及逆转软骨破坏带来了希望,其能抑制T效应细胞和其他免疫细胞,同时激活调节性T细胞,减少促炎细胞因子的产生,从而抑制炎症和减轻疼痛。白朝奇等[115]学者应用关节镜清理术联合自体骨髓间充质干细胞移植治疗膝骨关节炎,能显著减轻患者疼痛程度,下调患侧膝关节液内炎症递质(白细胞介素1β、肿瘤坏死因子α、前列腺素E2)的释放,改善患侧膝关节功能。CHAHAL等[116]的研究表明,骨髓间充质干细胞治疗可使骨关节炎患者疼痛和症状得到全面改善,并减少滑膜炎症。BASTOS 等[117]比较了有无富血小板血浆的骨髓间充质干细胞关节内注射与皮质类固醇关节内注射治疗膝骨关节炎的临床和实验室结果,显示3组患者在随访12个月时膝关节损伤及骨关节病治疗效果评分均有显著改善;与皮质类固醇组相比,骨髓间充质干细胞组和骨髓间充质干细胞+富血小板血浆组的膝关节损伤及骨关节病治疗效果评分改善率最高,说明关节内注射骨髓间充质干细胞可有效改善膝骨关节炎的功能,减轻症状。另外,有研究表明,间充质干细胞旁分泌的营养因子是间充质干细胞治疗骨关节炎的重要机制之一,作为遗传信息载体的外泌体参与许多疾病生理过程,可能在关节组织修复治疗中发挥作用[118-119]。 基因疗法是指通过将编码抗炎因子或生长因子等基因转导入关节内的细胞(关节软骨细胞或滑膜细胞),从而改善关节退行性变和抑制炎症反应来保护关节内环境,修复损伤的关节软骨。将目的基因导入关节软骨细胞或滑膜细胞来进行基因治疗是目前的趋势[120-121],骨关节炎的基因治疗正从实验室走向临床,随着有效目的基因的筛选、安全高效的载体和基因长期表达等问题的逐步解决,将有望治愈骨关节炎。"
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