Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (26): 4198-4203.doi: 10.12307/2021.121
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Peng Hongcheng1, Hua Zhen2, Wang Jianwei2
Received:
2020-05-15
Revised:
2020-05-19
Accepted:
2020-07-11
Online:
2021-09-18
Published:
2021-05-12
Contact:
Wang Jianwei, MD, Chief physician, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi 214071, Jiangsu Province, China
E-mail:wangjianwei1963@126.com
About author:
Peng Hongcheng, Master candidate, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Supported by:
CLC Number:
Peng Hongcheng, Hua Zhen, Wang Jianwei. MicroRNA-21 — an important regulator of bone regeneration and various bone diseases[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(26): 4198-4203.
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2.1 miR-21的生物生成 目前miRNA的生成包括两个步骤:在细胞核中产生前体miRNA,并将前体miRNA加工成细胞质中成熟的miRNA。具体而言,miR-21是由位于TMEM49基因的内含子区域中含有miR-21的基因编码,在细胞核中通过RNA聚合酶Ⅱ转录产生初级转录物pri-miR-21,然后在核酸内切酶Drosha及其辅因子DiGeorge关键区基因8的加工下,形成60-70 nt的具有发夹结构的前体miRNA(pre-miR-21),此后该前体通过核转运受体exportin 5通过核孔转运到细胞质中。在细胞质中,前体miR-21被核酸内切酶Dicer加工成一对20碱基的miRNA双链,然后释放形成成熟的miRNA链和互补的乘客链(miRNA*)。然而,由于单链成熟miRNA的热稳定性差,易与其他相互作用的蛋白质(如Dicer、TAR-RNA结合蛋白和Argonaute蛋白)一起组装成RNA诱导的沉默复合物(RISC),随后与之形成功能性的miRISC复合物,进而通过与靶信使RNA(mRNA)上的3′-非翻译区结合启动相关基因调控[3]。 2.2 miR-21在骨骼肌生长发育及血管重构中的作用 骨骼肌的生长发育、修复再生过程复杂,主要是成肌细胞增殖分化、多核肌管融合和成肌纤维、肌肉生成,过程中除了大量生长因子及肌源性调节因子参与外,现研究表明,miRNAs也作为重要的调节因子参与其中,如miR-1/206、miR-133a/133b、miR-124等。例如,在针对miR-21的实验研究中,CHEN等[4]通过脊椎动物斑马鱼生长发育的研究,发现miR-21对骨骼肌组织也存在差异表达,特别是在胚胎很早期就开始表达,并且达到所有miRNA的40%。还有对猪骨骼肌生长研究也证实miR-21对肌纤维形成生长有一定促进作用,转化生长因子β诱导基因作为miR-21的一个靶基因,可能通过转化生长因子β/MAPK信号通路,在miR-21的作用下形成正反馈回路,促进肌细胞的增殖分化[5]。另外,在失神经骨骼肌萎缩的研究中,作者认为miR-21作用于转化生长因子β1/Smad信号通路上的转化生长因子β1、转化生长因子β受体2、Smad7靶点,通过抑制miR-21的表达,其靶基因Smad7表达下调,所观察到的小鼠腓肠肌肌纤维面积增加[6]。此外,HAIDER等[7]研究发现miR-21在大鼠骨骼肌中介导细胞外信号调节激酶1/2(extracellular signal-regulated kinase 1/2,ERK1/2)-信号转导及转录激活因子3信号通路,通过调控下游基因白细胞介素11,增加大鼠骨骼肌中单位体积的血细胞数,对肌原细胞也有促进作用。 除了介导骨骼肌的生长,miR-21在血管重构中也起着重要的调节作用。有研究表明,miR-21可以通过调控内皮细胞的凋亡而影响其生理功能,进一步研究发现可能通过其靶基因磷酸酶及张力蛋白同源基因(phosphatase and tensin homology deleted on chromosome ten,PTEN)发挥促进内膜增生的作用,以及通过抑癌基因程序性死亡因子4激活ERK/核因子κB p65细胞信号通路抗内皮细胞凋亡[8-10],并且血流剪切力可以影响内皮细胞miR-21的表达[11]。miR-21还能干预血管平滑肌细胞的增殖和迁移,作者发现抑制miR-21能抑制细胞增殖,其作用可能是通过血小板衍生因子BB调 控[8]。此外,王飞[12]采用EdU增殖检测与Annexin V-PE/7-AAD的方法检测分析发现抑制miR-21表达会明显促进血管调控成纤维细胞和肌成纤维细胞的凋亡,并且是通过Caspase-3途径诱导发生。作为人类基因组中能间接调控缺氧诱导因子1α和血管内皮细胞生长因子表达的miRNA之一,miR-21很可能是临床上治疗血管损伤修复的潜在靶点。 2.3 miR-21介导骨再生和稳态的作用 骨再生是通过多种细胞和信号分子调控,将受损组织修复到其原始状态的生物学事件,在此过程中,组织修复活动涉及成骨细胞、破骨细胞、骨细胞和血管内皮细胞等。骨再生由细胞间通讯调控,越来越多的研究表明miRNA和外泌体在骨重塑中具有调节作用。例如,有研究发现骨髓微环境中的骨祖细胞中Dicer1缺损可抑制成骨细胞分化并诱导骨髓增生异常综合征和急性髓细胞性白血病[13];由于Dicer作为miRNA加工中的关键酶,侧面证实了miRNA在骨再生和重塑的调控作用。事实上,进一步研究表明,miR-21及其外泌体miR-21直接参与调节骨髓间充质干细胞、成骨细胞和破骨细胞的表达,调节着骨组织的动态平衡[14]。 2.3.1 miR-21调节成骨细胞分化 近年来研究表明,miRNAs能干预多种细胞的成骨分化,在骨再生过程中调节其转录因子及靶基因表达,其中miR-21在成骨细胞分化中具有重要作用。研究发现,骨髓间充质干细胞作为一种能在不同诱导条件下具有向不同细胞系进行多向分化潜能的干细胞,miR-21能够促进其成骨分化及体内异位成骨能力[15]。早期研究表明,miR-21上调增加了大鼠骨髓间充质干细胞中的骨桥蛋白和碱性磷酸酶的表达,并且促进成骨矿化[16]。此外,研究还表明,miR-21促进体内外的成骨作用,通过miR-21-5p进一步证实了这种作用。miR-21-5p促进成骨细胞分化标志物(Ⅰ型前胶原氨基末端前肽、Runx2和骨钙素)的生成,对成骨细胞分化具有正向调控作用[17]。随后,其他研究显示敲除小鼠miR-21基因后,骨髓间充质干细胞成骨分化能力减弱,成骨矿化基质差,小鼠颅骨形成受损,从而验证miR-21是成骨分化的正向调控因子[18]。 越来越多研究表明,miR-21通过靶向特定靶基因调节成骨,其中一个靶基因是Spry2,它是成骨细胞分化的关键调控因子。杨楠[19]发现过表达miR-21可以通过抑制受体酪氨酸激酶信号通路的调节基因Spry2和ERK/MAPK信号传导的相互作用上调成骨相关基因核心结合因子亚单位α1,促进间充质干细胞的成骨分化。此后,进一步研究表明,Spry1也是人脊髓间充质干细胞miR-21的重要靶点,抑制miR-21直接与Spry1的3′UTR位点结合能促进Spry1蛋白表达,显著降低成骨特异性基因Runx2和Osterix的表达,负向调控MAPK/ERK、成纤维细胞生长因子介导骨髓间充质干细胞的成骨分化[20]。此外,还发现miR-21作为内源性调节因子能够精确调控骨形态发生蛋白9介导的信号转导,通过激活Smad1/5/8使其磷酸化,并与Smad4结合促进成骨相关转录因子的表达[21-22]。另有报道miR-21靶点是Smad家族的成员。在WEI等[23]的研究中,Smad5作为上游调节位点,miR-21过表达下调人牙周膜干细胞中Smad5蛋白水平,负向促进Runx2、碱性磷酸酶、成骨细胞特异性转录因子和骨钙素29的表达。更重要的是,研究还发现Smad7可以激活核因子κB和STAT1抑制转化生长因子β信号,miR-21能调节该靶蛋白促进成骨细胞分化和矿化,由此可见,miR-21与转化生长因子β通路可通过Smad7形成正反馈调节闭合回路[24-25]。最后,研究表明激活素受体Ⅱb也是miR-21的靶基因,WEI等[26]在研究机械牵张对牙周膜干细胞中miRNAs的表达与成骨作用时,发现通过增强或抑制miR-21水平,可以调节机械拉伸对牙周膜组织中激活素受体Ⅱb蛋白水平的抑制作用,从而改变牙周膜干细胞的成骨分化。由此可见,miR-21是一个机械敏感基因。 2.3.2 miR-21调节破骨细胞分化 破骨细胞是来源于造血干细胞-单核-巨噬细胞系的多核骨吸收细胞[27],同成骨细胞一样在骨再生重建中扮演重要角色,两者相互调节支持骨内稳态。研究报道,破骨细胞的形成和分化受到核因子κB受体激活剂配体(receptor activator of NF-κB ligand,RANKL)和巨噬细胞集落刺激因子的调控[28]。与此相关的是,最近有研究表明了miR-21在控制破骨细胞形成和分化方面具有重要调节作用。例如,WANG等[29]在研究RANKL诱导RAW264.7破骨细胞前体细胞分化过程中,发现miR-21通过干预靶基因PTEN这个负性调节因子,激活PI3K/Akt信号通路,从而促进破骨细胞生成和骨吸收。此外,研究证实转录因子c-Fos能上调miR-21的表达,一方面通过活化蛋白1与miR-21结合促破骨细胞分化[30],另一方面降低抑癌基因程序性死亡因子4蛋白的表达,进而消除c-Fos对RANKL诱导下破骨细胞生成的抑制作用,因此,c-Fos/miR-21/PDCD4形成一个调控破骨细胞生成的正反馈通路[31]。更多研究表明,miR-21能靶向Fas配体介导破骨前作用;亦能靶向Spry1调节成骨细胞ERK信号,间接调控RANKL和骨保护素的表达水平[32-33]。综上表明,miR-21是miRNAs中调节破骨细胞分化的重点因子。 2.3.3 miR-21对成骨-破骨细胞的偶联作用 目前许多研究已经证实miR-21在成骨细胞和破骨细胞中的双重作用,但对于其偶联作用的研究尚不明朗,缺少系统模型。例如,miR-21在骨髓间充质干细胞、脐血间充质干细胞等中能靶向不同位点、信号通路促进成骨分化,然在牙周膜组织间充质干细胞中却抑制成骨分化潜能。miR-21现已被明确是前体细胞向成骨细胞分化的重要调控因子,SMIESZEk等[34]通过建立MC3T3与4B12的间接共同培养模型研究miR-21如何分化成骨细胞和破骨细胞之间的旁分泌作用,研究表明成骨细胞中miR-21抑制可能减少破骨细胞存活所需的旁分泌信号[35],进而影响细胞外基质矿化。进一步研究还发现miR-21抑制对骨桥蛋白、骨钙素和Runx-2等成骨标志物mRNA水平的影响,这些成骨相关基因反过来影响破骨-成骨细胞之间的相关作用,例如,Runx-2对不同成骨分化时期的正负反馈不同,可能miR-21作为其调节因子的作用也随其发生改变;miR-21的抑制与骨桥蛋白减少有关,会影响破骨细胞存活,而骨桥蛋白对旁分泌信号产生的成骨抑制效应又会抑制骨矿化形成[36]。miR-21的表达抑制减弱了前成骨细胞的旁分泌活性,这可能与前破骨细胞凋亡增加有关,而这种双重作用很有可能是由于RANKL(受RUNX-2控制表达)、骨桥蛋白的动态调节导致。因此,miR-21对成骨-破骨细胞的偶联作用还需要建立更多稳定的模型来进一步研究。 2.4 miR-21在骨骼疾病中的作用 骨疾病是由于骨内环境稳态遭到破坏所致。例如,骨再生重塑功能下降所致的骨质疏松症、关节间机械磨损所致无菌性骨关节炎症、肿瘤因子介入生长所致的多发性骨髓瘤和骨肉瘤等。近年来,越来越多的研究表明,miRNAs在疾病中起着重要的调控作用。下面简述miR-21在肌肉骨骼疾病发病机制中的作用,包括绝经后骨质疏松症、骨肉瘤及多发性骨髓瘤等疾病。 2.4.1 骨质疏松 骨质疏松症是在单位体积内骨量减少,骨再生与骨吸收的动态平衡紊乱,目前它作为一种多发慢性病,缺少有效的预防治疗方案。近年来,研究表明miR-21在骨质疏松患者血清中存在差异性表达,因此被视为治疗骨质疏松症的新靶点。重要的是,miR-21与雌激素缺乏的绝经后骨质疏松症密切相关,在实验研究中绝经后骨质疏松症患者血液中肾上腺髓质素和细胞因子信号转导抑制分子的表达显著下调,推测绝经后骨质疏松症与下调的肾上腺髓质素通过减少成骨细胞增殖和下调的细胞因子信号转导抑制分子3可能抑制破骨细胞形成有关[37]。 miR-21作为成骨细胞的正向调节因子已经在许多研究中报道,这些研究不仅表明miR-21可能是骨质疏松症潜在的治疗靶点,而且还能作为骨质疏松症的诊断工具。的确,ZHAO等[38]证明了miR-21在骨质疏松症患者中呈低水平表达,其促成骨分化的作用能够有效防治骨质疏松症。此外,KELCH等[39]研究发现miR-21-5p与骨密度显著相关,并且可以清楚区分非骨质疏松、骨质减少和骨质疏松患者,因此,miR-21可作为骨质疏松症高度敏感的生物标记物应用于临床诊断。这些研究为miR-21靶向骨质疏松的诊断与治疗提供了令人信服的数据支撑。 2.4.2 骨肉瘤 骨肉瘤是一种源于间充质干细胞的恶性骨肿瘤,具有成骨分化和类骨再生的特点。目前,由于骨肉瘤生长快、转移强、治愈率低的特点,许多研究者不断探究其新型治疗方式。有趣的是,多数miRNAs作为肿瘤抑制因子和癌基因被证实在骨肉瘤发展和转移中具有调节作用。最近研究表明miR-21能负性调节肿瘤抑制基因和凋亡蛋白(重组人原肌球蛋白1、抑癌基因程序性死亡因子4、组织金属蛋白酶抑制因子3、人凋亡相关因子配体、人不均一核核糖核蛋白K和PTEN)的表达[40]。Zhao等[41]研究85例骨肉瘤患者发现骨组织中miR-21的表达显著上调,是骨肉瘤早期诊断的良好生物标记物。进一步研究发现,miR-21通过调节RECK信号通路下游分子或RECK基因的甲基化影响骨肉瘤侵袭和转移。实验研究证实miR-21能通过抑制其靶基因磷酸酶基因激活PI3K/Akt通路,调节骨肉瘤转移和生存[42]。此外,研究还发现miR-21-5p通过直接靶向X-特异性转录本序列中的基因结合位点调节抑癌基因程序性死亡因子4的表达,抑制骨肉瘤细胞生长和转移[43]。总之,miR-21在骨肉瘤中有着明确的分子特征,因此,miR-21作为新的生物标志物和治疗靶点对临床预后诊疗有着重要影响。 2.4.3 多发性骨髓瘤 多发性骨髓瘤是一种源于B细胞系的恶性血浆肿瘤,具有骨髓浆细胞增殖和单克隆免疫球蛋白增生的特点。在疾病进展中,多发性骨髓瘤细胞释放可溶性因子影响间充质干细胞和成骨细胞的表达,进而出现多处溶骨性骨损伤,显著增加病理性骨折风险。如今越来越多研究证实了miR-21对多发性骨髓瘤的发生、发展及预后有着至关重要的影响。 CHENG等[44]研究证实,多发性骨髓瘤患者浆细胞中的miR-21水平明显高于正常对照组。研究还报道多发性骨髓瘤外泌体中含有高表达的miR-21,显著调节间充质干细胞的增殖、癌相关成纤维细胞转化和白细胞介素6的分泌,有助于支持多发性骨髓瘤存活[45]。更进一步研究其机制,miR-21能够介导Spry2基因靶标抑制ERK1/2的磷酸化,从而抑制多发性骨髓瘤的细胞生长和血管生成[46]。此外,PTEN、RECK等抑癌基因以及PI3K/Akt/eNOS/VEGF、FIH/HIF、MAPK/ERK等信号通路治疗多发性骨髓瘤正在被广泛研究。因此,miR-21可能是未来治疗多发性骨髓瘤的新方向。 2.4.4 其他骨相关疾病 随着对miRNAs的深入研究,发现miR-21在其他骨相关疾病中也有着作为生物标志物与治疗靶点的潜能。例如,HOSHIKAWA等[47]在关节内注射miR-21抑制剂发现对膝骨关节炎疼痛有显著镇痛作用,研究证实滑膜组织释放的miR-21能通过TLR7激活骨关节炎的炎性疼痛,因此抑制miR-21能够为骨关节炎提供新的镇痛方式。在一项系统的回顾性研究中,miR-21被证实是强直性脊柱炎中一种能诱导破骨细胞活化并导致骨质丢失的miRNA,具体机制可能是通过JAK2/STAT3信号通路的相互作用介导强直性脊柱炎的炎症和骨形成过程[48]。此外,潘东晟等[49]假设miR-21能够调控椎间盘变性中髓核细胞的自噬活动,实验观察到细胞中PTEN、PI3K及AKT的蛋白表达显著提高,差异有显著性意义。故此,miR-21能靶向沉默PTEN,促进PI3K和AKT发生磷酸化,从而激活PTEN/PI3K/AKT信号通路,最终抑制椎间盘退变细胞自噬。尽管目前对miR-21在骨疾病中的发生进展机制还未研究透彻,但miRNAs作为骨相关疾病的基因靶点为临床诊治开启了新思路。"
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