Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (29): 4697-4702.doi: 10.12307/2021.171
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Li Zhao, Cai Yuqiang
Received:
2020-11-19
Revised:
2020-11-27
Accepted:
2020-12-31
Online:
2021-10-18
Published:
2021-07-22
Contact:
Cai Yuqiang, Master, Chief physician, Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
About author:
Li Zhao, Master candidate, Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
Supported by:
CLC Number:
Li Zhao, Cai Yuqiang. Advances in exosome miRNAs in bone reconstruction and bone metabolic diseases[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(29): 4697-4702.
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2.1 骨源性外泌体的特性 在骨重建微环境中,骨源性外泌体含有特定的成骨蛋白,如骨形成蛋白1-7、碱性磷酸酶和真核细胞起始因子2,还含有非胶原基质蛋白,如骨涎蛋白、骨桥蛋白、骨钙素和骨黏素[8]。另外,外泌体还含有与破骨细胞分化相关的蛋白,如核因子κB受体活化因子配基(receptor activator of NF-κB ligand,RANKL)和核因子κB受体活化因子(receptor activator of NF-κB,RANK)[9]。骨源性外泌体中存在骨相关miRNAs,如miR-24、let-7、miR-143-3p、miR-10b-5p、miR-199b、miR-218和miR-214-3p,这些miRNAs在成骨细胞分化中起到重要的作用[10]。研究发现miRNAs可被选择性地装载到外泌体中,运输特定的信息,并通过调节细胞间通讯参与骨稳态[11]、免疫反应[12]、肿瘤生存[13]、应激反应[14]、血管生成等[15]。 2.2 外泌体miRNA在骨重建及骨代谢细胞通讯中的关系 骨源性外泌体以邻近细胞为靶细胞,与其他细胞和组织进行交流。miRNAs已被证实是骨重建及骨代谢中重要的转录后调节因子[16],扮演着旁分泌/内分泌的角色,并通过外泌体分泌到微环境中,介导细胞间的通讯。 2.2.1 破骨细胞-破骨细胞 骨是一种代谢活跃的组织,骨组织通过破骨细胞主导的矿化骨吸收和成骨细胞主导的骨基质合成而不断重塑。成骨细胞参与骨基质的合成和矿化,对维持骨骼系统的强度做出贡献。成骨细胞还通过旁分泌调节骨内稳态[17]。破骨细胞来源外泌体的一个主要特征是存在核酸(如miRNAs),在与靶细胞膜融合后,内化的miRNAs与相应的mRNAs结合以调节基因表达[18]。有研究在破骨细胞衍生的外泌体中发现了let-7E、miR-21、miR-155、miR-210、 miR-223和miR-378等miRNAs,其中miR-210和miR-223存在高水平表达。在这些miRNAs中,miR-210与调节细胞周期、分化、发育、膜运输、迁移、黏附的各种基因有关[19],miR-223的过表达阻碍了破骨细胞的分化[20],miR-378可以促进细胞存活并参与血管形成。有学者通过免疫亲和纯化分析,在32个破骨细胞来源外泌体中检测到1个RANK,在破骨细胞分化后期,RANK在基质小泡中的表达较高。然而,来自破骨细胞前体的外泌体不包含RANK,来自破骨细胞的外泌体通过竞争性RANKL-RANK相互作用以抑制破骨细胞前体分化[21]。 2.2.2 成骨细胞-破骨细胞 骨骼稳态的维持在很大程度上依赖于成骨细胞和破骨细胞之间通过RANKL-RANK相互作用的细胞通讯[22]。研究显示,破骨细胞可以通过与自身衍生的外泌体融合,实现与成骨细胞间的交流,从而抑制成骨细胞的骨形成[23]。这些含有miRNAs的外泌体通过自分泌和旁分泌机制传递信号,以调节骨重建的具体过程,但仍需进一步深入研究。从RAW264.7细胞释放的外泌体已经被证实其介导的成骨细胞-破骨细胞双向通讯在骨重建中具有重要作用[21]。来自成骨细胞的微血管(UAMS-32P)可以与破骨细胞结合,此过程中,绿色荧光蛋白标记的慢病毒载体转染UAMS-32P细胞后,将来源于细胞膜的基质小泡膜用绿色荧光蛋白标记,当与这些微血管共同培养时,破骨细胞前体表达绿色荧光蛋白,这表明成骨细胞-破骨细胞之间存在通讯[24]。同时,破骨细胞也将自身的外泌体传递给成骨细胞,以调节成骨细胞的活动[11]。 miR-214-3p是一种特异的miRNA前体,通过靶向成骨相关转录因子,抑制C2C12成肌细胞的成骨分化[25],并与重要的成骨转录因子ATF4相互作用抑制骨形成。此外, miR-214-3p通过靶向磷酸酶和张力蛋白同源物,通过PI3K/Akt途径促进破骨细胞的形成。LI等[11]在体内外的研究结果表明,破骨细胞miR-214-3p水平升高和血清外泌体miR-214-3p水平升高与骨形成减少有关。破骨细胞中的miR-214-3p以外泌体包裹的形式释放,这种外泌体miR-214-3p能够转移到成骨细胞,抑制成骨细胞的骨形成,促进破骨细胞的分化。Sun等[21]报道了另一种机制,破骨细胞来源外泌体miR-214可以在局部或通过血流到达远处,通过EwitinA2/EphA2介导的破骨细胞-成骨细胞相互作用来抑制成骨细胞的活性。因此,破骨细胞和成骨细胞之间的分子通讯很可能是由破骨细胞衍生的外泌体调节的。尽管破骨细胞来源外泌体可以附着在靶细胞膜上,通过相应受体诱导细胞内信号传递,但人们也认识到破骨细胞来源的微泡甚至是凋亡小体在细胞间通讯中可能也具有类似的生理和病理作用。 2.2.3 成骨细胞-骨细胞 骨细胞是终末分化细胞,在骨重建中发挥多功能作用[26]。研究发现,几种miRNAs如miR-218、miR-29、miR-484和miR-221存在于由小鼠骨细胞(MLO-Y4细胞)衍生的外泌体中[27]。在牙本质基质蛋白1驱动的白喉毒素受体转基因小鼠中,这些miRNAs在外泌体中的表达降低,这一发现表明骨细胞来源外泌体可以在体内循环。肌肉分泌肌肉抑制素来下调外泌体miR-218水平,这些外泌体通过靶向Wnt信号分子如Tcf7和SOST,抑制成骨细胞的分化[28],这一发现表明骨细胞来源外泌体中的miRNAs是一种新的肌肉-骨通讯机制。 2.2.4 骨髓间充质干细胞-骨髓间充质干细胞 骨髓间充质干细胞是最有效的外泌体生产工厂。最近研究表明,骨髓间充质干细胞来源外泌体除了表达CD9、CD63和CD81等跨膜标记蛋白之外,在骨源性外腔中还发现了各种核酸[28]。XU等[29]表征了人骨髓间充质干细胞成骨分化过程中外泌体miRNAs的差异表达,他们从骨髓间充质干细胞分离的外泌体中共检测到79种miRNAs,在不同时间点培养的骨髓间充质干细胞中发现了9种外泌体相关的miRNAs(let-7a、miR-199b、miR-218、miR-148a、miR-135b、miR-203、 miR-219、miR-299-5p和miR-302b)表达上调,4种miRNAs表达下调,并且进一步验证了5种miRNAs(miR-199b、 miR-218、miR-148a、miR135b和miR-221)在单个外泌体样本的差异表达。此外,还发现7种mRNA(RPS2、DGKA、ACIN1、DKK2、Xsox17、DDX6和Lsm2)在分化的骨髓间充质干细胞来源外泌体中随着时间的推移而差异表达。生物信息学分析表明,与RNA降解、mRNA监视、Wnt信号和RNA转运相关的途径与成骨分化相关,提示骨髓间充质干细胞来源外泌体中的miRNAs是成骨细胞分化的重要调节因子。ZHAO等[30]研究使用人间充质干细胞来源外泌体可诱导未分化的人间充质干细胞向成骨方向分化。从正常人间充质干细胞中分离出的外泌体可触发并增强人间充质干细胞中骨形态发生蛋白9和转化生长因子β1这两种成骨诱导因子的表达。此外,成骨激活的人间充质干细胞来源外泌体在诱导人间充质干细胞成骨分化方面有较好的反应,这些结果表明,人间充质干细胞来源外泌体可以很容易地被受体细胞内吞,与Ⅰ型胶原和纤维连接蛋白等细胞外基质蛋白结合,并在体外和体内触发未分化的人间充质干细胞谱系特异性分化[31]。移植的骨髓间充质干细胞来源外泌体可以“驱动”相邻骨髓间充质干细胞的功能;外源性骨髓间充质干细胞来源外泌体被摄取并促进内源性骨髓间充质干细胞的成骨分 化[32]。骨髓间充质干细胞来源外泌体miR-151-5p靶向内源性骨髓间充质干细胞,促进成骨分化并挽救受损的个体发育分化和减少成脂分化[33]。 2.2.5 骨髓间充质干细胞-成骨细胞 骨髓间充质干细胞通过旁分泌途径在成骨细胞分化中发挥重要作用[34]。QIN等[33]研究证明骨髓间充质干细胞来源外泌体能正向调控人成骨细胞的分化,他们发现miR-196A、miR-27A和miR-206在人骨髓间充质干细胞来源外泌体中高表达并都具有成骨作用,其中miR-196A对成骨细胞分化和成骨基因表达的影响最大,此外也发现与miR-196A抑制剂共干预可以有效减弱这些外泌体的成骨效应。成骨细胞也可通过外泌体向骨髓间充质干细胞发送信息,矿化成骨细胞来源外泌体(MC3T3-E1细胞)可被骨基质细胞(ST2细胞)吸收,这些外泌体通过激活Wnt信号促进骨髓间充质干细胞向成骨细胞分化,来源于老龄小鼠骨髓间质液的外泌体可以通过降低血红素加氧酶1(Hmox1)水平来抑制年轻骨髓间充质干细胞的成骨分化[35]。 2.2.6 骨髓间充质干细胞-免疫细胞 免疫细胞和骨细胞之间的串扰积极地参与骨重建及骨代谢过程。骨髓间充质干细胞来源外泌体在细胞通讯中起免疫调节介质的作用。骨髓间充质干细胞来源外泌体与T细胞融合并调节其成熟、凋亡和增殖[36-38]。然而,来自树突状细胞等免疫细胞的外泌体由人骨髓间充质干细胞内吞,并促进它们的招募和迁移[39]。来自单核细胞的外泌体刺激骨髓间充质干细胞的成骨分化[28]。 2.3 疾病条件下外泌体miRNA介导骨代谢的调节 伴随类风湿性关节炎的慢性关节炎症以及骨关节炎的关节软骨机械退化似乎都涉及了关节间隙内循环的外泌体miRNAs变化。外泌体miRNAs可作为骨质疏松症和骨关节炎的潜在生物标志物,同时在骨代谢疾病的靶向治疗方面也发挥了有益的作用。 2.3.1 骨质疏松症 骨质疏松症是因骨量减少、骨微结构恶化,以致骨脆性增高及骨折危险性增加的一种全身性骨病,严重威胁老年尤其是绝经期妇女的健康。在一项研究中,与对照组相比,低骨量绝经后妇女血清中miR-21-5p表达下 调[40]。MARTIN等[41]研究表明人骨髓间充质干细胞诱导的脂肪细胞和人骨髓间充质干细胞诱导的成骨细胞之间通过外泌体的RNA进行转化,他们观察到人骨髓间充质干细胞诱导的成骨细胞与人骨髓间充质干细胞诱导的脂肪细胞孵育后,成脂相关因子PPARγ、瘦素、CEBPα和CEBPδ转录增加,抗成骨相关miRNA如miR-138、miR-30c、miR-125a、miR-125b、miR-31表达增加,可能与骨钙素、骨桥蛋白表达降低有关,并且患者血浆中的miR-31也升高,微泡miR-31被间充质干细胞摄取,并通过降低Frizzled-3水平来抑制成骨分化,这表明外泌体可能是调控成骨细胞和脂肪细胞之间竞争以预防或治疗骨质疏松症和其他骨量减少症的目标成分[42]。QIU 等[43]体内实验表明,骨髓间充质干细胞来源外泌体减轻了骨质疏松症,外泌体中miR-1503p上调进一步改善了骨质疏松,而外泌体中miR-150-3p下调则损害了骨质疏松。体外实验表明,骨髓间充质干细胞外泌体促进成骨细胞增殖和分化并抑制细胞凋亡,外泌体miR-150-3p升高可增强成骨,而外泌体miR-150-3p抑制则可破坏成骨。此研究证实了外泌体miR-150-3p在骨质疏松症中促进成骨细胞增殖和分化,并为骨质疏松症患者的治疗提供了新的线索。 2.3.2 骨关节炎 骨关节炎的发病机制复杂,主要是环境和遗传因素相互作用,其涉及关节各个组织中软骨的逐渐退化、滑膜病变、骨重塑和血管生成[44]。骨关节炎的早期诊断很困难,且治疗选择有限,目前的研究集中于铁蛋白或滑膜细胞来源外泌体在骨关节炎病理中的作用[45]。当用白细胞介素1β处理成纤维样滑膜细胞时,外泌体中miR-500B、 miR-4454、miR-720、miR-199B和miR-3154水平升高[46]。有学者将骨关节炎患者关节液中的外泌体与非骨关节炎患者的外泌体进行了比较,骨关节炎组外泌体中miR-200C增加了2.5倍,而在氧化应激条件下miR-200C表达上调,并间接抑制E盒结合锌指蛋白1(ZEB1),后者在维持关节软骨方面有重要作用。此外,外泌体miRNA图谱揭示了女性和男性患者之间存在性别特异性,女性骨关节炎患者的外泌体中存在多种雌激素反应的miRNAs,如miR-181D-3p、miR-185-5p、 miR-26a和miR-7107-5p,研究表明女性骨关节炎的发病率高于男性,骨关节炎患者外泌体来源miRNAs数据可能提供了一些分子机制来解释这种差异,也表明这些外泌体miRNAs可以作为女性骨关节炎的特异性诊断标志物[47]。还有研究表明雌激素可以增加针对Toll样受体3的miR-26a表达,而雌激素抑制剂则抑制成纤维样滑膜细胞中的miR-26a表达[47],miR-26a和miR-26b等miRNAs水平与骨关节炎严重程度呈负相关,提示监测miRNAs可进一步作为追踪骨关节炎进展的生物标志物[48]。有研究将miR-140-5p转染滑膜间充质干细胞(SMSC-140),收集高表达SMSC-140的外泌体,用于治疗骨关节炎,他们发现这些miR-140-5p富集的外泌体通过交替的Wnt信号激活YAP,促进了关节软骨细胞的增殖和迁移,而不会阻碍体外细胞外基质的分泌。此外,这些外泌体在大鼠模型中成功地预防了骨关节炎[49]。CHEN等[50]在创伤性骨关节炎软骨组织的临床样品中检测到E74样因子3表达增加,而miR-136-5p表达减少。骨髓间充质干细胞衍生的外泌体显示出丰富的miR-136-5p水平,可被软骨细胞内化,并且miR-136-5p促进了软骨细胞的迁移,证实了miR-136-5p靶向E74样因子3,并可下调其表达。此外在创伤后骨关节炎小鼠模型中,外泌体miR-136-5p被发现可以减少软骨细胞外基质的变性。 有研究证实了滑膜间充质干细胞来源外泌体miR-155-5p可促进骨关节炎软骨细胞的增殖和迁移[51],抑制了细胞凋亡并增强了细胞外基质的分泌,并有效减缓了小鼠骨关节炎的发展,所以干细胞来源外泌体作为未来治疗骨代谢紊乱的靶向治疗策略具有广阔的潜力。 2.3.3 类风湿性关节炎 类风湿性关节炎是一种系统性自身免疫性疾病,主要累及滑膜关节[52]。有研究发现miR-155和miR-146a参与了类风湿性关节炎的发展[53],这两种miRNAs均受肿瘤坏死因子α刺激,间接影响炎症反应,miR-155促进炎症反应,而miR-146a则减轻炎症反应。与正常对照组相比,这两种miRNAs在类风湿性关节炎患者组都上调,当miR-155在体内被抑制时,肿瘤坏死因子α的产生就会减少。miR-155表达升高还与导致炎症状态的细胞因子产生增加有关[53-54]。miR-146a可能具有调节类风湿性关节炎患者免疫和炎症反应的能力。例如,miR-146a过表达抑制白细胞介素6和白细胞介素8,下调白细胞介素1β和与肿瘤坏死因子受体相关的蛋白[55-56]。在树突状细胞释放的外泌体中也发现了miR-155和miR-146a,当这些外泌体被受体树突状细胞摄取时,miR-155促进炎症基因表达,而miR-146a可降低炎症基因表达[53]。有学者发现,间充质干细胞衍生的外泌体参与miR-320a的细胞间转移并随后抑制类风湿性关节炎的进展[57],其研究结果为类风湿性关节炎治疗提供了一种新颖的潜在治疗方法。 "
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