Long noncoding RNAs are involved in osteoblast
differentiation and osteoclast production

doi:10.3969/j.issn.2095-4344.2553

Abstract

Abstract:

BACKGROUND: Long noncoding RNAs play a role in transcription and post-transcriptional levels, participate in the regulation of bone regeneration, and are closely related to osteoarthritis as well.

OBJECTIVE: To review the research progress of long noncoding RNAs in bone regeneration and osteoarthritis.

METHODS: A computer-based search of CNKI, PubMed, and Elsevier was performed for relevant articles regarding long noncoding RNAs in bone regeneration and osteoarthritis published from January 2000 to June 2019, including review, basic research and clinical research. The search terms were “LncRNA; bone; bone regeneration; osteoarthritis” in Chinese and English. After preliminarily reading titles and abstracts, irrelevant articles were excluded. According to the inclusion and exclusion criteria, 64 articles were finally included in result analysis.

RESULTS AND CONCLUSION: Bone regeneration is a complex process involving the interaction of osteoblasts and osteoclasts. Long noncoding RNAs are involved in the differentiation of osteoblasts and the production of osteoclasts, which play an important role in the balance of osteoblasts and osteoclasts. Therefore, it is a key molecule of bone regeneration. Long noncoding RNAs are involved in the occurrence and development of osteoarthritis and differentially expressed in osteoarthritis patients and healthy people, some of which are elevated and some are decreased in osteoarthritis patients. Thus, defining their respective expression differences and functions is of great significance for the prevention and treatment of osteoarthritis.

Key words: Long noncoding RNA, bone, bone regeneration, osteoarthritis, research progress

CLC Number:

Xiong Kun, Deng Jiang, Huang Wenliang, Yuan Cheng, Ruan Shiqiang, Ma Xianming, Li Maolun, Ding Chuan. Long noncoding RNAs are involved in osteoblast differentiation and osteoclast production[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(14): 2229-2234.

Figures/Tables 1

2.1 长链非编码RNA的分类和特征相关研究表明，人类基因组中仅有2%的RNA编码蛋白质，其余98%是非编码蛋白的RNA[21-22]。按相对分子质量大小，非编码RNA可分为两大类：一类是非编码的小RNA，另一类是长链非编码RNA[23-24]。长链非编码RNA是一类长度大于200个核苷酸的RNA分子，缺乏较明显的开放阅读框，因此具有较低甚至不具有翻译蛋白质的功能。根据基因组的位置，长链非编码RNA可以分为5类[25-27]：反义长链非编码RNA、内含子长链非编码RNA、基因区间的长链非编码RNA、启动子相关的长链非编码RNA、非翻译区的长链非编码RNA。虽然不同的长链非编码RNA具有不同的功能，但是其具有以下共同特征：①转录本的长度为200-100 000 nt，具有与mRNA相似的结构，剪接后存在聚尾和启动子的结构，在分化过程中，有一种动态表达机制和选择性剪接模式使其形成不同的长链非编码RNA[28]；②通常长链非编码RNA具有非编码潜力，但一些长链非编码RNA可以编码一些短肽[29]；③具有很低的守恒率[30]；④具有组织特异性和时空特异性[31]，不同组织中长链非编码RNA的表达量不同，相同的长链非编码RNA在同一组织不同状态下的表达也不同；⑤不同长链非编码RNA的丰度在不同的细胞中也不同[32]。 2.2 长链非编码RNA的作用模式随着对长链非编码RNA功能的逐渐了解，长链非编码RNA与靶基因相互作用的机制已成为研究热点。早期认为原位调节是长链非编码RNA沉默相邻基因转录的惟一机制，其主要是通过招募染色质修饰复合物来实现的。近年来随着对长链非编码RNA了解的深入，其作用机制可归纳为4种：表观遗传、转录调控、转录后调控以及其他特定的调控模式。 2.2.1 长链非编码介导表观遗传修饰长链非编码RNA可以将染色质重塑复合物募集到特定位点，然后调节靶向基因的表达。来自HOXC基因座的HOTAIR募集染色质重塑复合物PRC2并将其定位于HOXD位点，从而诱导HOXD基因座的亲本遗传沉默[33-35]。类似地，lncRNAs Xist和Kcnq1ot可以通过重构复合物如甲基转移酶Ezh2或G9a募集[36-38]，以实现相关基因的表观遗传沉默。 2.2.2 长链非编码RNA介导转录调控长链非编码RNA可通过各种机制在转录水平沉默基因的表达。长链非编码RNA可以干扰相邻基因的转录。例如，在酵母中SER3基因的转录受其上游lncRNA SRG1的影响[39]。长链非编码RNA可通过阻断启动子区域来干扰基因表达。例如，lncRNA DHFR可以在DHFR基因的启动子区域形成RNA-DNA3螺旋结构[40]，抑制转录因子TFIID的结合，从而抑制DHFR基因表达。此外，长链非编码RNA可与RNA结合蛋白相互作用并靶向启动子区，调节基因表达。例如，位于CCND1启动子上游的长链非编码RNA可以调节RNA结合蛋白TLS的活性并影响CCND1的表达[41]。长链非编码RNA还可以调节转录因子的活性，如lncRNA Evf2可与转录因子D1x2形成转录复合物以激活D1x6表达[42-43]。长链非编码RNA还可以通过调节基本转录因子来控制基因表达。例如，Alu RNA可以通过抑制RNA聚合酶Ⅱ来实现广泛的基因抑制[44]。 2.2.3 长链非编码RNA介导转录后调控长链非编码RNA可以在转录后水平与mRNA形成双链RNA复合物，掩盖mRNA的主要顺式作用元件，从而调节基因表达。例如，lncRNA Zeb2(Sip1)能够在由HOX位点转录mRNA内含子的5'末端剪切位点处形成双链，从而防止内含子被剪切。该区域含有表达Zeb2蛋白所必需的核糖体结合位点，Zeb2反义RNA可以这种方式增加Zeb2蛋白的表达。这表明长链非编码RNA可以指导mRNA同种型的可变剪接。长链非编码RNA与mRNA竞争结合miRNA结合位点，导致miRNA靶分子的上调。LncMD作为海绵状分子分离miR-125b与靶分子IGF mRNA的结合，促进间充质干细胞分化为肌肉细胞[45]。 2.2.4 长链非编码RNA介导其他特定的调控模式此外，长链非编码RNA的复性(退火)具有靶向作用，允许蛋白质受体复合物识别有义链的mRNA转录物。该模式类似于通过siRNA靶向mRNA的RNA诱导沉默复合物(RISC)。来自互补转录物的双链RNA，甚至是结合扩展内部发夹结构的长链非编码RNA，可以加工成内源siRNA以沉默基因表达。 2.3 与成骨细胞相关的长链非编码RNA 2.3.1 H19 H19(印迹母系表达转录物)是在用成骨诱导培养基诱导原始干细胞期间高度上调的基因之一。它位于11p15.5，长度为2.3 kb，在进化过程中相对保守，在调节生物功能方面发挥重要作用。H19是miR-675的前体，它可以由Drosha和Dicer以剪接依赖的模式产生2种成熟的miRNA(miR-675-5p和miR-675-3p)。人间充质干细胞成骨分化过程中H19和miR-675表达上调，miR-675的上调不仅可以下调TGF-β1，还可以抑制Smad3的磷酸化，从而下调HDAC4/5导致HDAC减少[46]，促进成骨。LIANG等[47]发现H19作为miR-141和miR-22的内源竞争性ceRNA，直接与miR-141和miR-22结合，阻止miR-141和miR-22对Wnt/β-catenin的抑制作用，从而促进成骨分化。HUANG等[48]报道H19和miR-675过表达抑制脂肪分化。miR-675与组蛋白去乙酰化酶HDAC4-6(脂肪分化的必需分子)的3'-UTR区域靶向结合从而下调HDAC4-6的表达，抑制脂肪的分化。最近的研究还表明，H19在胚胎胎盘生长和细胞分化中起着关键的作用。 2.3.2 ANCR ANCR(抗分化非编码RNA)是一种新型的长链非编码RNA，在干细胞分化期间其表达下调，这是使成骨细胞保持在未分化状态所必需的。研究证实ANCR与成骨细胞分化密切相关[49]。最近发现通过siRNA技术靶向沉默ANCR可以增加成骨细胞分化标志物的水平，如碱性磷酸酶和骨钙蛋白，而过表达ANCR则能够降低成骨细胞中这些标志物的表达。机制上，已有研究证实ANCR通过募集EZH2来调节RUNX2的表达，EZH2主要是通过在RUNX2基因启动子中催化H3赖氨酸-27三甲基化，抑制RUNX2的表达以及随后的成骨细胞分化，进一步的研究也证实了ANCR与EZH2的直接关系。最近的研究也证明了下调ANCR水平能够促进牙周膜干细胞的成骨分化，其能够上调成骨标志物如碱性磷酸酶、骨钙蛋白和RUNX2的表达[50]，其可能的机制是ANCR通过控制经典的Wnt信号传导途径从而来影响牙周膜干细胞的成骨分化，但是还缺乏足够的证据证实是该通路发挥作用的，需要进一步的实验验证。 2.3.3 MALAT1 MALAT1(转移相关肺腺癌转录本1)位于11q13.1，长度为8 545 nt，首先发现与肺腺癌的转移呈正相关。XIAO等[51]证明了MALAT1促进钙化性主动脉瓣疾病(CAVD)中主动脉瓣膜间质细胞的成骨分化，进一步的研究表明MALAT1作为miR-204的海绵分子发挥作用引起Smad4表达上调，Smad4的上调促进碱性磷酸酶和下游分子骨钙素的表达，从而促进骨形成和矿化。 2.3.4 MODR MODR是上颌窦干细胞成骨过程中上调的长链非编码RNA，沉默MODR后可以引起RUNX2表达的下调。MODR主要是作为与miR-454结合的分子海绵来缓解其对RUNX2的抑制，从而上调RUNX2表达并促进成骨作用[52]。 2.4 与破骨细胞相关的长链非编码RNA 骨形成是一种动态和持续的塑造、修复和重建过程。维持骨平衡主要取决于成骨细胞参与的新骨形成和破骨细胞参与的骨吸收过程，两者缺一不可，相互作用。破骨细胞是来源于造血干细胞或单核细胞/巨噬细胞前体细胞的多核细胞，其分化过程包括多个阶段。DOU等[53]用RANKL(100 μg/L)和M-CSF(50 μg/L)诱导RAW264.7细胞的成骨分化，通过检测诱导过程中相关基因的表达，发现了circRNA、miRNA、长链非编码RNA和mRNA的一系列变化。该研究小组进一步构建了142对与mRNA之间具有相关联的长链非编码RNA，发现长链非编码RNA也参与了造血干细胞向破骨细胞分化的调控，从而提示长链非编码RNA与破骨细胞的形成和分化密切相关。骨质疏松症是与骨矿化减少相关的常见疾病，其主要是由于破骨细胞骨吸收超过成骨细胞的骨形成。TONG等[54]报道了长链非编码RNA DANCR参与外周血中单核细胞的形成，并与人类骨质疏松症有关，其机制主要是促进白细胞介素6和肿瘤坏死因子α的表达从而增加骨吸收。这些结果表明长链非编码RNA也参与破骨细胞的骨吸收过程。 2.5 长链非编码RNA与骨关节炎的关系骨关节炎是一种慢性退行性关节病，是最常见的关节炎形式，主要表现为关节软骨的退化、软骨下骨的改变、邻近骨的广泛重塑以及骨赘的形成。骨关节炎的发病机制不详，这给临床预防和治疗骨关节炎带来了巨大的挑战。目前公认的几大危险因素主要是年龄、性别、肥胖、生物化学因素和生物力学因素。治疗骨关节炎主要采取的是阶梯治疗方法：即改变生活方式、物理治疗-关节腔注射皮质醇或者透明质酸-手术治疗。虽然采取阶梯治疗的方法在一定程度上能够缓解患者的症状和改善生活质量，但是其远期效果不佳，不能从根本上预防和治疗该疾病。因此，探究和阐明骨关节炎的发病机制有助于更加有效地控制该疾病的发生和发展。近年来，长链非编码RNA的研究成为一大热点，越来越多的研究也发现长链非编码RNA与骨关节炎的发生、发展有密切的联系。目前，运用基因芯片以及其他一些手段已经检测到骨关节炎患者中长链非编码RNA表达的异常，其中部分长链非编码RNA表达上调，部分表达降低。XING等[55]发现6种长链非编码RNAs(HOTAIR、GAS5、PMS2L2、RP11-445H22.4、H19和CTD-2574D22.4)的表达在骨关节炎软骨中上调，并且可能通过增加MMP-9、MMP-13、BMP-2和ADAMTS5的mRNA表达来促进骨关节炎的发生和发展。ZHANG等[56]也报道了HOTAIR的上调，通过促进白细胞介素1β诱导的MMP表达和软骨细胞凋亡来促进骨关节炎的发生和发展。长链非编码RNA CIR(软骨损伤相关的长链非编码RNA)在骨关节炎患者软骨中异常表达，主要在受损区域表达增加，其在软骨细胞外基质的降解过程中起关键作用[57-59]。该长链非编码RNA可以充当siRNA本身并且可以诱导mRNA形成内源siRNA从而抑制波形蛋白的表达，波形蛋白的下调能够促进细胞外基质的降解并削弱关节软骨的完整性从而导致骨关节炎的发展。SU等[60]研究了来自骨关节炎患者和健康受试者的MEG3(肿瘤抑制因子)表达并且还进一步深入研究了骨关节炎患者中MEG3的表达和血管内皮生长因子的潜在关系。他们证实了骨关节炎患者中MEG3的表达显著降低，而血管内皮生长因子的表达显著增加，血管内皮生长因子已被证明可调节生长板软骨的肥厚软骨重塑、骨化和血管侵犯。因此可得出结论：MEG3的表达与骨关节炎中血管内皮生长因子的表达呈负相关，MEG3的下调可能与骨关节炎的发生发展有关。KANG等[61]证明了前列腺癌基因表达标记(PCGEM)和miR-145的相互抑制关系。他们研究发现了PCGEM可以通过充当miR-770的海绵来刺激骨关节炎滑膜细胞的增殖。在另一项研究中，PEARSON等[62]发现了一种长链非编码RNA，被称为与p50相关的COX-2外源RNA(PACER)，其在骨关节炎中增加并且被认为是骨关节炎软骨组织中产生炎症和疼痛的介质。SONG等[63]发现GAS5(肿瘤抑制因子)在骨关节炎软骨细胞中上调，其上调增加了几种基质金属蛋白酶的表达水平(如MMP-2，MMP-3，MMP-9，MMP-13)，这些基质金属蛋白酶是软骨退化和骨关节炎进展的关键因素。KIM等[64]报道了miR-101和长链非编码RNA HOTTIP是骨关节炎发病机制中的一种新型调节因子。他们发现HOTTIP的上调(HoxA基因的已知调节因子)和miR-101的下调在软骨内骨化和骨关节炎进展过程中起着重要的作用。miR-101的下调导致在关节软骨细胞(包括整合素1)上表达的胶原结合整联蛋白下调，并促进软骨的破坏。 "

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