外泌体非编码RNA在骨关节炎发病机制中的研究进展

doi:10.3877/cma.j.issn.1674-134X.2023.04.009

外泌体是由多种细胞分泌的一种直径在50~150纳米的细胞外囊泡，在生理和病理状态下发挥旁分泌、免疫调节和细胞间通信等重要作用。研究发现，外泌体中以微小RNA和长链非编码RNA为代表的非编码RNA参与了对骨关节炎发病机制的调控。其原理是，微小RNA可以结合信使RNA并影响其转录及相应的蛋白翻译过程，而长链非编码RNA可以竞争性结合微小RNA并抑制微小RNA对信使RNA转录的调控，进而影响下游靶基因的表达，最终影响细胞凋亡和增殖、影响软骨细胞外基质代谢及调控炎症反应等多个方面，实现其对骨关节炎发病的调控作用。对于外泌体非编码RNA的研究将有助于进一步了解骨关节炎发病机制、延缓病情进展、促进软骨损伤修复以及促进针对性治疗的发展。

关键词: 外泌体, RNA，未翻译, 微RNAs, RNA，长链非编码, 骨关节炎

Exosomes are extra-cellular vesicles with a diameter of 50-150 nm secreted by a variety of cells. They play an important role in paracrine, immune regulation and inter-cellular communication under physiological and pathological conditions. Studies have shown that non-coding RNAs (ncRNA) such as micro RNAs (miRNA) and long non-coding RNAs (ncRNA) in exosomes are involved in the regulation of osteoarthritis (OA) pathogenesis. The mechanisms are as follows: miRNA can bind messenger RNA (mRNA) and affect its transcription and the following translation, while lncRNA can competitively bind miRNA and inhibit the regulation of miRNA on mRNA transcription. In this way, ncRNA can regulate the expression of downstream target genes, affecting cell apoptosis and proliferation, regulating chondrocyte extracellular matrix metabolism, and regulating inflammation responses and therefore regulating the pathogenesis of osteoarthritis. The research of exosomal ncRNA will help to further understand the pathogenesis of OA, delay the progression of OA, promote the repair of cartilage damage and promote the development of targeted therapy.

Key words: Exosomes, RNA, untranslated, MicroRNAs, RNA, long noncoding, Osteoarthritis

图1 外泌体的合成、释放与摄取注：细胞通过胞吞作用形成早期核内体，并结合细胞内的mRNA、蛋白质等物质转化为晚期核内体，以腔内膜囊的形式与细胞膜融合，并通过胞吐作用释放到细胞外空间，最终形成外泌体。释放的外泌体通过胞吞作用、与细胞膜上受体的相互作用或与细胞膜直接融合等方式被靶细胞摄取

Figure 1 Synthesis, release and uptake of exosomes

表1 调控软骨细胞凋亡和增殖的外泌体ncRNA

Table 1 Exosomal ncRNAs regulating apoptosis and proliferation of chondrocytes

ncRNA种类	促进软骨细胞增殖或抑制软骨细胞凋亡	抑制软骨细胞增殖或促进软骨细胞凋亡
miRNA	miR-210^[20]，miR-8485^[21]，miR-320c^[22]，miR-291a-3p^[28]，miR-196a-5p^[28]，miR-23a-3p^[28]，miR-24-3p^[28]	miR-34a^[15,16]，miR-108a^[15]，miR-384-5p^[17]，miR-181a^[18]，miR-146b^[19]，miR-206^[23,27]，miR-27a-3p^[26]
lncRNA	lncRNA KLF3-AS1^[23]，lncRNA ZFAS1^[24]，lncRNA PACER^[25]，lncRNAFOXD2-AS1^[26,27]	lncRNA Nespas^[28]，lncRNA PVT1^[29,30]

表1 调控软骨细胞凋亡和增殖的外泌体ncRNA

Table 1 Exosomal ncRNAs regulating apoptosis and proliferation of chondrocytes

ncRNA种类	促进软骨细胞增殖或抑制软骨细胞凋亡	抑制软骨细胞增殖或促进软骨细胞凋亡
miRNA	miR-210^[20]，miR-8485^[21]，miR-320c^[22]，miR-291a-3p^[28]，miR-196a-5p^[28]，miR-23a-3p^[28]，miR-24-3p^[28]	miR-34a^[15,16]，miR-108a^[15]，miR-384-5p^[17]，miR-181a^[18]，miR-146b^[19]，miR-206^[23,27]，miR-27a-3p^[26]
lncRNA	lncRNA KLF3-AS1^[23]，lncRNA ZFAS1^[24]，lncRNA PACER^[25]，lncRNAFOXD2-AS1^[26,27]	lncRNA Nespas^[28]，lncRNA PVT1^[29,30]

表2 调控关节软骨ECM代谢的外泌体ncRNA

Table 2 Exosomal ncRNAs that regulate extracellular matrix metabolism of chondrocytes

ncRNA种类	促进ECM合成或抑制ECM降解	抑制ECM合成或促进ECM降解
miRNA	miR-221^[33]，miR-145^[34]，miR-4784^[35]，miR-29a^[36]，miR-140^[37]，miR-27b^[38]	miR-483-5p^[31]，miR-16-5p^[32]
lncRNA	lncRNA KLF3-AS1^[39]	lncRNA CIR^[38]
circRNA	circSERPINE2^[43,44]	circ_0136474^[41]，circ_CDR1as^[42]

表2 调控关节软骨ECM代谢的外泌体ncRNA

Table 2 Exosomal ncRNAs that regulate extracellular matrix metabolism of chondrocytes

ncRNA种类	促进ECM合成或抑制ECM降解	抑制ECM合成或促进ECM降解
miRNA	miR-221^[33]，miR-145^[34]，miR-4784^[35]，miR-29a^[36]，miR-140^[37]，miR-27b^[38]	miR-483-5p^[31]，miR-16-5p^[32]
lncRNA	lncRNA KLF3-AS1^[39]	lncRNA CIR^[38]
circRNA	circSERPINE2^[43,44]	circ_0136474^[41]，circ_CDR1as^[42]

表3 调控关节内炎症反应的外泌体ncRNA

Table 3 Exosomal ncRNAs regulating inflammation in joints

ncRNA种类	抑制关节内炎症反应	加剧关节内炎症反应
miRNA	miR-149^[47]，miR-138^[49]，miR-216a-5p^[51]，miR-12496^[52]	miR-26a-5p^[45]
lncRNA	lncRNA GACAT3^[50]，lncRNA PACER^[25]	lncRNA DANCR^[51]，lncRNA HOTAIR^[52]，lncRNA LOC101928134^[53]

表3 调控关节内炎症反应的外泌体ncRNA

Table 3 Exosomal ncRNAs regulating inflammation in joints

ncRNA种类	抑制关节内炎症反应	加剧关节内炎症反应
miRNA	miR-149^[47]，miR-138^[49]，miR-216a-5p^[51]，miR-12496^[52]	miR-26a-5p^[45]
lncRNA	lncRNA GACAT3^[50]，lncRNA PACER^[25]	lncRNA DANCR^[51]，lncRNA HOTAIR^[52]，lncRNA LOC101928134^[53]

图2 lncRNA、miRNA与mRNA的相互作用机制注：外泌体中的miRNA、lncRNA进入细胞后，miRNA与mRNA上的位点结合，通过影响下游基因的表达，调控软骨细胞增殖或凋亡、关节内炎症反应和软骨细胞外基质代谢。而lncRNA与miRNA的作用位点结合，使miRNA从与mRNA的结合位点上分离，从而阻断或降低miRNA对mRNA表达的调控作用

Figure 2 The interacting mechanism of lncRNA, miRNA and mRNA

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Research progress of exosomal non-coding RNA in pathogenesis of osteoarthritis

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Research progress of exosomal non-coding RNA in pathogenesis of osteoarthritis