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

[1]	Ratneswaran A, Kapoor M. Osteoarthritis year in review: genetics, genomics, epigenetics[J]. Osteoarthritis Cartilage, 2021, 29(2): 151-160.
[2]	HRashed M, Bayraktar E, KHelal G, et al. Exosomes: from garbage bins to promising therapeutic targets[J/OL]. Int J Mol Sci, 2017, 18(3): 538. DOI: 10.3390/ijms18030538.
[3]	Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes[J/OL]. Science, 2020, 367(6478): eaau6977. DOI: 10.1126/science.aau6977.
[4]	Samanta S, Rajasingh S, Drosos N, et al. Exosomes: new molecular targets of diseases[J]. Acta Pharmacol Sin, 2018, 39(4): 501-513.
[5]	Chang YH, Wu KC, Harn HJ, et al. Exosomes and stem cells in degenerative disease diagnosis and therapy[J]. Cell Transplant, 2018, 27(3): 349-363.
[6]	Elahi FM, Farwell DG, Nolta JA, et al. Preclinical translation of exosomes derived from mesenchymal stem/stromal cells[J]. Stem Cells, 2020, 38(1): 15-21.
[7]	Antimisiaris SG, Mourtas S, Marazioti A. Exosomes and exosome-inspired vesicles for targeted drug delivery[J/OL]. Pharmaceutics, 2018, 10(4): 218. DOI: 10.3390/pharmaceutics10040218.
[8]	Liang Y, Xu X, Li X, et al. Chondrocyte-targeted microRNA delivery by engineered exosomes toward a cell-free osteoarthritis therapy[J]. ACS Appl Mater Interfaces, 2020, 12(33): 36938-36947.
[9]	文星钊，张志奇. 非编码RNA在骨关节炎中的研究进展[J/CD]. 中华关节外科杂志(电子版), 2020, 14(2): 189-195.
[10]	Chen JQ, Papp G, Szodoray P, et al. The role of microRNAs in the pathogenesis of autoimmune diseases[J]. Autoimmun Rev, 2016, 15(12): 1171-1180.
[11]	Mo YY. microRNA regulatory networks and human disease[J]. Cell Mol Life Sci, 2012, 69(21): 3529-3531.
[12]	Derrien T, Johnson R, Bussotti G, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression[J]. Genome Res, 2012, 22(9): 1775-1789.
[13]	Kristensen LS, Andersen MS, Stagsted LVW, et al. The biogenesis, biology and characterization of circular RNAs[J]. Nat Rev Genet, 2019, 20(11): 675-691.
[14]	Kim GB, Seo MS, Park WT, et al. Bone marrow aspirate concentrate: its uses in osteoarthritis[J/OL]. Int J Mol Sci, 2020, 21(9): 3224. DOI: 10.3390/ijms21093224.
[15]	Cheleschi S, Tenti S, Mondanelli N, et al. microRNA-34a and microRNA-181a mediate visfatin-induced apoptosis and oxidative stress via NF-κBpathway in human osteoarthritic chondrocytes[J/OL]. Cells, 2019, 8(8): 874. DOI: 10.3390/cells8080874.
[16]	Yang B, Ni J, Long H, et al. IL-1β-induced miR-34a up-regulation inhibits Cyr61 to modulate osteoarthritis chondrocyte proliferation through ADAMTS-4[J]. J Cell Biochem, 2018, 119(10): 7959-7970.
[17]	Zhang W, Cheng P, Hu W, et al. Inhibition of microRNA-384-5p alleviates osteoarthritis through its effects on inhibiting apoptosis of cartilage cells via the NF-κB signaling pathway by targeting SOX9[J]. Cancer Gene Ther, 2018, 25(11-12): 326-338.
[18]	Zhai X, Meng R, Li H, et al. miR-181a modulates chondrocyte apoptosis by targeting glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L) in osteoarthritis[J]. Med Sci Monit, 2017, 23: 1224-1231.
[19]	Liu X, Liu L, Zhang H, et al. miR-146b accelerates osteoarthritis progression by targeting alpha-2-macroglobulin[J]. Aging, 2019, 11(16): 6014-6028.
[20]	Li Z, Meng D, Li G, et al. Overexpression of microRNA-210 promotes chondrocyte proliferation and extracellular matrix deposition by targeting HIF-3α in osteoarthritis[J]. Mol Med Rep, 2016, 13(3): 2769-2776.
[21]	Li Z, Wang Y, Xiang S, et al. Chondrocytes-derived exosomal miR-8485 regulated the Wnt/β-catenin pathways to promote chondrogenic differentiation of BMSCs[J]. Biochem Biophys Res Commun, 2020, 523(2): 506-513.
[22]	Sun H, Hu S, Zhang Z, et al. Expression of exosomal microRNAs during chondrogenic differentiation of human bone mesenchymal stem cells[J]. J Cell Biochem, 2019, 120(1): 171-181.
[23]	Liu Y, Lin L, Zou R, et al. MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis[J]. Cell Cycle, 2018, 17(21-22): 2411-2422.
[24]	Ye D, Jian W, Feng J, et al. Role of long noncoding RNA ZFAS1 in proliferation, apoptosis and migration of chondrocytes in osteoarthritis[J]. Biomedecine Pharmacother, 2018, 104: 825-831.
[25]	Jiang M, Liu J, Luo T, et al. LncRNA PACER is down-regulated in osteoarthritis and regulates chondrocyte apoptosis and lncRNA HOTAIR expression[J/OL]. Biosci Rep, 2019, 39(6): BSR20190404. DOI: 10.1042/BSR20190404.
[26]	Wang Y, Cao L, Wang Q, et al. LncRNA FOXD2-AS1 induces chondrocyte proliferation through sponging miR-27a-3p in osteoarthritis[J]. Artif Cells Nanomed Biotechnol, 2019, 47(1): 1241-1247.
[27]	Cao L, Wang Y, Wang Q, et al. LncRNA FOXD2-AS1 regulates chondrocyte proliferation in osteoarthritis by acting as a sponge of miR-206 to modulate CCND1 expression[J]. Biomedecine Pharmacother, 2018, 106: 1220-1226.
[28]	Park S, Lee M, Chun CH, et al. The lncRNA, nespas, is associated with osteoarthritis progression and serves as a potential new prognostic biomarker[J]. Cartilage, 2019, 10(2): 148-156.
[29]	Zhao Y, Zhao J, Guo X, et al. Long non-coding RNA PVT1, a molecular sponge for miR-149, contributes aberrant metabolic dysfunction and inflammation in IL-1β-simulated osteoarthritic chondrocytes[J/OL]. Biosci Rep, 2018, 38(5): BSR20180576. DOI: 10.1042/BSR20180576.
[30]	Li Y, Li S, Luo Y, et al. LncRNA PVT1 regulates chondrocyte apoptosis in osteoarthritis by acting as a sponge for miR-488-3p[J]. DNA Cell Biol, 2017, 36(7): 571-580.
[31]	Wang H, Zhang H, Sun Q, et al. Intra-articular delivery of antago-miR-483-5p inhibits osteoarthritis by modulating matrilin 3 and tissue inhibitor of metalloproteinase 2[J]. Mol Ther, 2017, 25(3): 715-727.
[32]	Li L, Jia J, Liu X, et al. microRNA-16-5p controls development of osteoarthritis by targeting SMAD3 in chondrocytes[J]. Curr Pharm Des, 2015, 21(35): 5160-5167.
[33]	Zheng X, Zhao FC, Pang Y, et al. Downregulation of miR-221-3p contributes to IL-1β-induced cartilage degradation by directly targeting the SDF1/CXCR4 signaling pathway[J]. J Mol Med, 2017, 95(6): 615-627.
[34]	Hu G, Zhao X, Wang C, et al. microRNA-145 attenuates TNF-α-driven cartilage matrix degradation in osteoarthritis via direct suppression of MKK4[J/OL]. Cell Death Dis, 2017, 8(10): e3140. DOI: 10.1038/cddis.2017.522.
[35]	Liu J, Yu Q, Ye Y, et al. Abnormal expression of miR-4784 in chondrocytes of osteoarthritis and associations with chondrocyte hyperplasia[J]. Exp Ther Med, 2018, 16(6): 4690-4694.
[36]	Li X, Zhen Z, Tang G, et al. miR-29a and miR-140 protect chondrocytes against the anti-proliferation and cell matrix signaling changes by IL-1β[J]. Mol Cells, 2016, 39(2): 103-110.
[37]	Grigelioniene G, Suzuki HI, Taylan F, et al. Gain-of-function mutation of microRNA-140 in human skeletal dysplasia[J]. Nat Med, 2019, 25(4): 583-590.
[38]	Li YF, Li SH, Liu Y, et al. Long noncoding RNA CIR promotes chondrocyte extracellular matrix degradation in osteoarthritis by acting as a sponge for mir-27b[J]. Cell Physiol Biochem, 2017, 43(2): 602-610.
[39]	Zhang LQ, Zhao GZ, Xu XY, et al. Integrin-β1 regulates chondrocyte proliferation and apoptosis through the upregulation of GIT1 expression[J]. Int J Mol Med, 2015, 35(4): 1074-1080.
[40]	Xiao K, Xia Z, Feng B, et al. Circular RNA expression profile of knee condyle in osteoarthritis by illumina HiSeq platform[J]. J Cell Biochem, 2019, 120(10): 17500-17511.
[41]	Li Z, Yuan B, Pei Z, et al. Circ_0136474 and MMP-13 suppressed cell proliferation by competitive binding to miR-127-5p in osteoarthritis[J]. J Cell Mol Med, 2019, 23(10): 6554-6564.
[42]	Zhang W, Zhang C, Hu C, et al. Circular RNA-CDR1as acts as the sponge of microRNA-641 to promote osteoarthritis progression[J/OL]. J Inflamm, 2020, 17: 8. DOI: 10.1186/s12950-020-0234-y.
[43]	Crowe N, Swingler TE, Le LT, et al. Detecting new microRNAs in human osteoarthritic chondrocytes identifies miR-3085 as a human, chondrocyte-selective, microRNA[J]. Osteoarthritis Cartilage, 2016, 24(3): 534-543.
[44]	Haseeb A, Makki MS, Khan NM, et al. Deep sequencing and analyses of miRNAs, isomiRs and miRNA induced silencing complex (miRISC)-associated miRNome in primary human chondrocytes[J/OL]. Sci Rep, 2017, 7(1): 15178. DOI: 10.1038/s41598-017-15388-4.
[45]	Jin Z, Ren J, Qi S. Human bone mesenchymal stem cells-derived exosomes overexpressing microRNA-26a-5p alleviate osteoarthritis via down-regulation of PTGS2[J/OL]. Int Immunopharmacol, 2020, 78: 105946. DOI: 10.1016/j.intimp.2019.105946.
[46]	Li ZC, Han N, Li X, et al. Decreased expression of microRNA-130a correlates with TNF-α in the development of osteoarthritis[J]. Int J Clin Exp Pathol, 2015, 8(3): 2555-2564.
[47]	Santini P, Politi L, Vedova PD, et al. The inflammatory circuitry of miR-149 as a pathological mechanism in osteoarthritis[J]. Rheumatol Int, 2014, 34(5): 711-716.
[48]	Makki MS, Haseeb A, Haqqi TM. microRNA-9 promotion of interleukin-6 expression by inhibiting monocyte chemoattractant protein-induced protein 1 expression in interleukin-1β-stimulated human chondrocytes[J]. Arthritis Rheumatol, 2015, 67(8): 2117-2128.
[49]	朱旭，苑博，赵增同，等. 膝骨关节炎中微小RNA-138与缺氧诱导因子-2α表达及意义[J/CD]. 中华关节外科杂志(电子版), 2021, 15(2): 192-198.
[50]	Li X, Ren W, Xiao ZY, et al. GACAT3 promoted proliferation of osteoarthritis synoviocytes by IL-6/STAT3 signaling pathway[J]. Eur Rev Med Pharmacol Sci, 2018, 22(16): 5114-5120.
[51]	Zhang L, Zhang P, Sun X, et al. Long non-coding RNA DANCR regulates proliferation and apoptosis of chondrocytes in osteoarthritis via miR-216a-5p-JAK2-STAT3 axis[J/OL]. Biosci Rep, 2018, 38(6): BSR20181228. DOI: 10.1042/BSR20181228.
[52]	Hu J, Wang Z, Shan Y, et al. Long non-coding RNA HOTAIR promotes osteoarthritis progression via miR-17-5p/FUT2/β-catenin axis[J/OL]. Cell Death Dis, 2018, 9(7): 711. DOI: 10.1038/s41419-018-0746-z.
[53]	Yang DW, Zhang X, Qian GB, et al. Downregulation of long noncoding RNA LOC101928134 inhibits the synovial hyperplasia and cartilage destruction of osteoarthritis rats through the activation of the Janus kinase/signal transducers and activators of transcription signaling pathway by upregulating IFNA1[J]. J Cell Physiol, 2019, 234(7): 10523-10534.

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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