miRNA与骨关节炎病理发展过程的相关性

doi:10.3969/j.issn.2095-4344.1297

摘要/Abstract

摘要：

文章快速阅读：

文题释义：

骨关节炎：是一种以关节软骨退行性变和关节炎症为特征的慢性骨关节疾病，主要临床表现为慢性疼痛和关节活动障碍，严重影响患者生活质量。骨关节炎是由机械、遗传和环境因素引起的复杂多因素疾病，也是关节中最常见的疾病，许多环境因素如激素、饮食、感染、创伤、酒精摄入和接触烟草烟雾等，都会增加骨关节炎的患病风险，年龄是其独立危险因素。

miRNA：是一类长19-25个碱基的内源性非蛋白编码RNA，具有高度保守性，主要通过与靶基因mRNA的3'非翻译区(3'-UTR)结合，降解mRNA靶基因或诱导翻译沉默，影响细胞的增殖、分化、凋亡及个体发育等。miRNA具有高度保守性，因此其转录过程与其他基因相互独立，在生物体内多种代谢过程中发挥调控作用，本身并不翻译蛋白质。

摘要

背景：越来越多的研究表明，miRNA在骨关节炎的病理发展过程中起着重要调控作用。

目的：综述miRNA与骨关节炎病理发展过程的相关性。

方法：应用计算机检索CNKI、PubMed等数据库建库至2018年12月有关miRNA与骨关节炎相关性研究的文献，中文关键词为“骨关节炎，微小RNA”，英文关键词为“osteoarthritis，miRNA”，进行全文检索。

结果与结论：miRNA与骨关节炎病理发展过程密切相关；miRNA异常表达参与了骨关节炎软骨细胞增殖、凋亡、关节软骨细胞外基质稳态、软骨细胞炎症及关节疼痛；异常表达的miRNA可作为骨关节炎早期诊断的标志物；miRNA作为一种调控基因在骨关节炎分子靶向治疗中具有广阔的应用前景。

中国组织工程研究杂志出版内容重点：人工关节；骨植入物；脊柱；骨折；内固定；数字化骨科；组织工程
ORCID: 0000-0002-7368-1121(王继成)

关键词: 骨关节炎, 微小RNA(miRNA), 异常表达, 软骨细胞, 细胞外基质, 炎症, 疼痛, 诊断, 治疗

Abstract:

BACKGROUND: More and more studies have shown that miRNA plays an important regulatory role in the pathological development of osteoarthritis.
OBJECTIVE: To review the correlation between miRNA and the pathological development of osteoarthritis.
METHODS: A computer-based search of CNKI and PubMed databases was conducted for the articles concerning miRNA and osteoarthritis published before December 2018. The keywords were “osteoarthritis, miRNA” in Chinese and English, respectively.
RESULTS AND CONCLUSION: miRNA is closely related to the pathogenesis of osteoarthritis. Abnormal expression of miRNA is involved in chondrocyte proliferation and apoptosis, articular cartilage extracellular matrix homeostasis, chondrocyte inflammation and joint pain in osteoarthritis. Abnormally expressed miRNA can be used as a marker for early diagnosis of osteoarthritis. As a regulatory gene, miRNA has broad prospects in molecular targeted therapy of osteoarthritis.

Key words: osteoarthritis, miRNA, abnormal expression, chondrocytes, extracellular matrix, inflammation, pain, diagnosis, treatment

中图分类号:

R459.9|R363.2+1

王继成，易智. miRNA与骨关节炎病理发展过程的相关性[J]. 中国组织工程研究, 2019, 23(24): 3875-3881.

Wang Jicheng, Yi Zhi.

Correlation between miRNA and pathological development of osteoarthritis

[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(24): 3875-3881.

图/表（结果） 3

2.1 miRNA的生成及生物学作用 早在1993年，有研究者在丽新小杆线虫(C.elegans)体内发现了第1个miRNA-lin-4^[9]，直到2000年，Reinhart等^[10]在哺乳动物体内发现了另一个具有转录后调节功能的小分子RNA:let-7。随着人们研究的不断深入，至今已发现1 000多种miRNA，每种miRNA调节多种mRNA，从而参与调控不同的生物过程^[11]。

miRNA生成是一个非常复杂的生物过程，其包括胞质合成和胞核合成2个部分，并需要多种酶的参与^[12]，见图2。首先，编码miRAN的基因在细胞核内经RNA聚合酶Ⅱ转录形成具有特殊发夹结构[多聚腺苷酸尾巴(AAAAA)和帽子结构(7MGpppG)]的pri-miRNA，接着核酸酶Drosha(核糖核酸酶Ⅲ)将pri-miRNA进行微切割并处理成具有茎环结构、大小为70-80 nt的miRNA前体，即pre-miRNA。在Ran-GTP辅助下，细胞质转运蛋白Exportins-5将pre-miRNA从细胞核内运输到细胞胞质中，然后由核糖核酸酶Ⅲ(Dicer酶)将其剪切成为大小为19-23 nt的miRNA:miRNA*复合结构。miRNA*通常被降解^[13-14]，而miRNA与AGO(argonaute)蛋白结合形成成熟miRNA。成熟的miRNA与RNA诱导的沉默复合物结合发挥其生物作用，包括2种方式：①miRNA与靶mRNA完全互补时，miRNA的作用方式是降解靶mRNA^[15-16]；②miRNA与靶mRNA不完全互补时，miRNA与3' UTRs结合抑制靶mRNA的翻译^[17-18]，导致相关蛋白表达水平降低。在人体中，miRNA与靶mRNA主要是不完全互补，对基因转录后的翻译进行调控。

2.2 骨关节炎的病理生理 骨关节炎的发病机制尚未完全明了，其发病与年龄、肥胖、感染及创伤等多种因素相关^[19]。有研究表明，软骨细胞外基质降解及软骨细胞过度凋亡导致的关节软骨退变，是骨关节炎的主要病理变化^[20]。软骨细胞是软骨组织中的主要细胞类型，其在维持骨骼、关节结构及功能方面发挥重要作用^[21-22]。细胞外基质主要由Ⅱ型胶原蛋白和聚集蛋白聚糖组成，成熟软骨细胞能够合成及分泌细胞外基质，其在维持细胞外基质合成代谢和分解代谢之间的动态平衡中发挥关键作用^[23-24]。有研究表明，基质金属蛋白酶13和具有血小板反应蛋白基序的解整合素和金属蛋白酶(recombinant a disintegrin and metalloproteinase with thrombospondin 5，ADAMTS-5)是导致细胞外基质降解的2种主要水解酶，而基质金属蛋白酶13主要降解Ⅱ型胶原蛋白^[25-28]。既往研究表明，过多的机械应激、炎症及促炎因子(白细胞介素1、白细胞介素6、肿瘤坏死因子α)参与了骨关节炎的病理过程^[29-30]。由促炎因子诱导的软骨损伤过程，包括软骨细胞外基质(细胞外基质)代谢紊乱、软骨稳态破坏和基质降解酶(如基质金属蛋白酶13)的表达增强^[31]。有研究报道，miRNA可通过调节炎症递质、血管内皮生长因子和神经生长因子的表达参与骨关节炎的病理过程^[32]。进一步的研究表明，miRNA可能抑制或促进基质金属蛋白酶和胶原蛋白的表达，导致细胞外基质降解和软骨细胞凋亡，最终导致骨关节炎^[33-34]。

2.3 miRNA在骨关节炎中的异常表达 Tew等^[35]对365例骨关节炎患者和健康者软骨组织中miRNA的表达谱进行了分析，发现有16个miRNA出现了差异表达；通过对723种miRNA进行分析发现^[36]，7种miRNA显示出统计学意义的差异表达，在这7种人类miRNA中，1种在骨关节炎软骨细胞(hsa-miR-483-5p)中上调，6种在正常软骨细胞中上调(hsa-miR-149*，hsa-miR-582-3p，hsa-miR-1227，hsa-miR-634，hsa-miR-576-5p和hsa-miR-641)；Zhang等^[37]的研究发现，在骨关节炎软骨组织中包括8个上调的miRNA(miR-193b、miR-199a-3p/hsa-miR-199b-3p、miR- 455-3p、miR-210、miR-381、miR-92a、miR-320c和miR-136)及4种下调的miRNA(miR-490-5p、miR-4287、miR-BART8 *和miR-US25-1*)。Marta等^[3]对19种miRNA表达的评估发现， miR-138-5p、miR-146a-5p、miR-335-5p和miR-9-5p的表达在骨关节炎中显著上调。Wang等^[38]的研究发现，miRNA-98在骨关节炎软骨组织中表达水平升高。Zhang等^[39]的研究发现，miR-21在骨关节炎软骨组织中过表达。Zhang等^[40]的研究发现，miR-502-5p在骨关节炎软骨组织中显著低表达。Song等^[41]的研究发现，miR-222在骨关节炎软骨组织中呈低表达。

2.4 miRNA与骨关节炎

2.4.1 miRNA与软骨细胞增殖、凋亡 Cao等^[42]研究发现，miR-15b通过靶向胰岛素样生长因子和胰岛素样生长因子受体抑制软骨细胞增殖，并通过靶向Bcl-2加速软骨细胞凋亡。Zhang等^[43]研究发现miR-34a在骨关节炎患者中呈过表达，miR-34a可直接抑制δ样蛋白1mRNA，导致骨关节炎软骨细胞中δ样蛋白1、总PI3K和p-AKT浓度下降，诱导细胞凋亡，在手术诱导的骨关节炎大鼠膝关节中，通过注射miR-34a拮抗剂可减弱关节软骨细胞死亡和软骨损伤。相关研究表明，抑制miR-34a表达能够解除白细胞介素1β诱导的Cyr61抑制，促进骨关节炎软骨细胞增殖^[44]。Zhang等^[45]发现miR-373在骨关节炎患者软骨细胞中表达下调，过表达miR-373通过抑制嘌呤能P2X7受体及炎性因子(如白细胞介素6和白细胞介素8)的表达来促进软骨细胞增殖。Wu等^[46]研究发现，miR-200b-3p通过抑制DNA甲基转移酶3α的表达抑制基质金属蛋白酶的分泌，促进Ⅱ型胶原的合成，进而促进骨关节炎软骨细胞的生长和增殖。He等^[47]研究发现，miR-20可通过PI3K/AKT/ mTOR信号通路靶向自噬相关基因10，抑制软骨细胞增殖和自噬。Shen等^[48]发现miR-30a-5p在骨关节炎患者软骨中高表达，其可通过靶向Akt基因阻断G₀/G₁期软骨细胞，诱导软骨细胞凋亡；Chen等^[49]研究表明，miR-29b-3p可通过靶向颗粒体蛋白前体促进软骨细胞凋亡和骨关节炎的发生，注射miR-29b-3p拮抗剂可延缓该过程。有研究表明，miR-98可能通过下调骨关节炎发病机制中Bcl-2的表达来促进软骨细胞凋亡和软骨降解^[50]。miRNA与骨关节炎软骨细胞增殖及凋亡的关系，见表1。

2.4.2 miRNA与关节软骨细胞外基质已有大量文献证实，基质金属蛋白酶13与ADAMTS-5是导致细胞外基质降解的2种主要水解酶，而基质金属蛋白酶13主要降解Ⅱ型胶原蛋白^[25-28]。

Li等^[51]研究发现miR-27a-3p在骨关节炎患者中表达下调，白细胞介素1β可通过MAPK和NF-κB途径抑制miR-27a-3p的活性，增加ADAMTS-5的表达，进而导致细胞外基质降解，促进骨关节炎的发生。Shi等^[52]发现miR-486-5p在骨关节炎患者中呈高表达，用miR-486-5p模拟物处理CHON-001人软骨细胞后，抑制了细胞的增殖和迁移，并且还抑制Ⅱ型胶原蛋白和聚集蛋白聚糖的表达，导致骨关节炎的发生。Xu等^[53]研究发现miR-483-5p在骨关节炎患者中呈过表达，其能够降低转化生长因子β1的表达，而敲除miR-483-5p则显著提高转化生长因子β1在mRNA和蛋白水平的表达，进一步的研究发现，过表达的miR-483-5p通过下调转化生长因子β1表达显著降低胶原蛋白和聚集蛋白聚糖mRNA的水平，并增加Runx2和基质金属蛋白酶13 mRNA的水平，这些发现表明miR-483-5p对维持软骨组织具有重要作用。Wei等^[54]研究发现骨关节炎软骨组织中miR-138水平显著降低，过表达miR-138能够抑制人骨关节炎软骨细胞和软骨形成SW1353细胞中p65、COX-2和白细胞介素6的蛋白质水平，延缓骨关节炎的进展。有研究发现miR-26a和miR-26b在骨关节炎患者中表达下调，用miR-26a或miR-26b抑制剂转染后，基质金属蛋白酶3、基质金属蛋白酶9、基质金属蛋白酶13和环加氧酶2的表达水平上调，进一步研究发现，miR-26a和miR-26b的下调可能通过促进NF-κB信号传导途径参与骨关节炎的发生^[55]。Mao等^[56]研究发现骨关节炎软骨中miR-92a-3p表达下调，miR-92a-3p能增强聚集蛋白聚糖、软骨寡聚蛋白和胶原蛋白启动子上的H3乙酰化，并且还促进软骨基质表达。研究发现骨关节炎患者中miR-105表达下调，并且与骨关节炎患者中上调的Runx2、ADAMTS-7和ADAMTS-12表达呈负相关^[57]。Ji等^[58]研究发现骨关节炎软骨中miR-30a与ADAMTS-5表达呈负相关，过表达miR-30a可显著抑制ADAMTS-5的表达。Wang等^[59]研究发现在骨关节炎软骨组织中，miR-411与基质金属蛋白酶13呈负相关，过表达miR-411能够显著抑制基质金属蛋白酶13的表达，延缓骨关节炎进程。Zhang等^[60]发现，miR-9的表达水平在骨关节炎患者软骨组织中显著降低，在骨关节炎大鼠膝关节腔内注射miR-9拮抗剂，可显著抑制骨关节炎大鼠软骨组织中基质金属蛋白酶13的表达，降低胶原降解并增强胶原蛋白，这说明miR-9可抑制基质金属蛋白酶13的表达水平，降低其对胶原蛋白的抑制作用，延缓骨关节炎病理过程。Kang等^[61]研究发现骨关节炎软骨中miR-23a-3p表达明显较高，SMAD3表达明显低于正常组织，进一步的研究发现，过表达的miR-23a-3p通过直接靶向SMAD3抑制Ⅱ型胶原蛋白和聚集蛋白聚糖的表达，进而促进骨关节炎进展。miRNA与关节软骨细胞外基质的关系，见表2。

2.4.3 miRNA与软骨细胞炎症 Ding等^[62]研究发现miR-93具有抑制炎症作用，使用脂多糖诱导软骨细胞损伤后，miR-93表达显著升高，主要抑制促炎细胞因子(包括肿瘤坏死因子α、白细胞介素1β和白细胞介素6)的表达来减弱炎症反应；进一步的研究发现，Toll样受体4是miR-93在软骨细胞中的直接靶标，miR-93通过Toll样受体4介导的NF-κB信号通路参与骨关节炎的炎症反应，miR-93拮抗剂可促进炎症的发生。Wang等^[63]研究发现，miR-142-3p表达在骨关节炎小鼠关节软骨组织中显著降低，过表达miR-142-3p可显著抑制NF-κB和促炎细胞因子的产生，包括白细胞介素1、白细胞介素6和肿瘤坏死因子α；高迁移率族蛋白1是骨关节炎的重要炎症递质，进一步的研究发现，miR-142-3p可通过抑制高迁移率族蛋白1介导的NF-κB信号通路，抑制骨关节炎中炎症细胞及炎症因子的表达。Tardif等^[64]发现miR-140在骨关节炎软骨细胞中低表达，过表达miR-140可显著抑制炎症反应。Yang等^[65]研究发现miR-365可促进骨关节炎关节软骨炎症因子的表达，诱导骨关节炎的发生及发展。

2.4.4 miRNA与关节疼痛绝大部分骨关节炎患者会出现关节疼痛，关节疼痛既是骨关节炎的主要临床症状，也是导致患者关节活动障碍的原因之一。周围疼痛感受器与中枢感觉系统之间的信号传导可导致疼痛。Wang等^[66]研究发现，miR-146a参与了骨关节炎关节疼痛，其通过对白细胞介素1受体相关激酶1和肿瘤坏死因子受体相关因子6进行调控，改变上述细胞因子的表达，进而影响神经细胞的分化与疼痛发生。既往研究发现，过表达miR-199a-3P可使骨关节炎动物模型中炎症因子表达上调，诱发疼痛效应，异常表达的miR-146a和miR-183能够加剧膝关节疼痛，miR-558在骨关节炎软骨组织中低表达，转染miR-558模拟物能抑制炎症因子的表达并减轻疼痛^[67]。

2.4.5 miRNA与骨关节炎早期诊断 Soyocak等^[34]研究发现骨关节炎患者血清中的miR-146a和miR-155表达明显高于健康对照组，且随骨关节炎的进程增加，因此miR-146a和miR-155可作为骨关节炎的辅助诊断标志物，骨关节炎病程越长其表达越高。既往研究发现let-7e在骨关节炎患者血清中低表达，其可作为诊断骨关节炎的标志物。同样有研究报道miR-4284和miR-1282可作为诊断骨关节炎的标志物^[67]。

2.4.6 miRNA与骨关节炎治疗 Cui等^[68]研究发现，miR-634可通过靶向PIK3R1基因调节PI3K/Akt/S6和PI3K/Akt/mTOR/S6轴来抑制骨关节炎软骨细胞的存活和基质合成，miR-634抑制剂可逆转该过程。Si等^[69]发现在骨关节炎大鼠模型关节腔内注射miR-140，能够调节大鼠的细胞外基质稳态，延缓骨关节炎进展，miR-14可能是一种新型潜在治疗靶点。Baek等^[70]研究发现miR-449a在骨关节炎中表达上调，在骨关节炎动物模型关节腔内注射锁核酸-抗-miR-449a能够增加软骨再生，Ⅱ型胶原蛋白和聚集蛋白聚糖表达水平升高，延缓了骨关节炎进展。

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