Precise targeting of miR-141/200c cluster in chondrocytes attenuates osteoarthritis development
Precise targeting of miR-141/200c cluster in chondrocytes attenuates osteoarthritis development
复制标题
软骨细胞中 miR-141/200c 簇的精确靶向可减弱骨关节炎的发展
DOI：
10.1136/annrheumdis-2020-218469
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发表时间：
2021-03-01
影响因子：
27.4
通讯作者：
Lu, Jun
中科院分区：
文献类型：
--
作者：
Ji, Ming-Liang;Jiang, Hua;Lu, Jun
尽管多年来进行了涉及骨关节炎（OA）的miRNA治疗的临床前研究，但这些miRNA中还没有一个转化为临床应用，这主要是由于缺乏有效的关节内（IA）递送系统。在这里，我们研究了软骨细胞特异性适体修饰的聚乙二醇化聚酰胺胺纳米颗粒（NPs）为基础的miRNAs交付OA的治疗效果。方法通过miR-141/200 c（flox/flox）小鼠和Col 2a 1-CreER（T2）; miR-141/200 c（flox/flox）小鼠检查miR-141/200 c簇在骨骼和OA发育过程中的作用。在小鼠关节和人软骨标本中进行组织学分析。设计了软骨细胞特异性适配子修饰的纳米粒，并对其渗透性、稳定性和安全性进行了评价。在通过NP IA注射用miR-141/200 c操纵使内侧半月板手术不稳定后，通过微CT分析、X射线和骨关节炎研究学会国际评分来评估OA进展。通过质谱分析、分子对接和分子动力学模拟研究了适配体与受体之间的相互作用。NP自由地和深度地渗透到小鼠和人软骨中，并且出乎意料地在软骨细胞中持续至少5周。OA软骨细胞微环境改善microRNA（miRNAs）的内/溶酶体逃逸。在治疗上，IA注射miR-141/200 c抑制剂提供了强有力的软骨保护，而miR-141/200 c的异位表达加剧了OA。miR-141/200 c通过靶向SIRT 1促进骨关节炎的发生，SIRT 1使白细胞介素6（IL-6）启动子中的组蛋白乙酰化，从而激活IL-6/STAT 3通路。结论我们的研究结果表明，这种纳米载体可以优化miR-141/200 c进入软骨细胞的转运动力学，促进miRNA特异性疾病修饰OA药物的开发。
Objectives Despite preclinical studies involving miRNA therapeutics conducted in osteoarthritis (OA) over the years, none of these miRNAs have yet translated to clinical applications, owing largely to the lack of efficient intra-articular (IA) delivery systems. Here, we investigated therapeutic efficacy of the chondrocyte-specific aptamer-decorated PEGylated polyamidoamine nanoparticles (NPs)-based miRNAs delivery for OA.Methods The role of miR-141/200c cluster during skeletal and OA development was examined by miR-141/200c(flox/flox) mice and Col2a1-CreER(T2); miR-141/200c(flox/flox) mice. Histological analysis was performed in mouse joints and human cartilage specimens. Chondrocyte-specific aptamer-decorated NPs was designed, and its penetration, stability and safety were evaluated. OA progression was assessed by micro-CT analysis, X-ray and Osteoarthritis Research Society International scores after destabilising the medial meniscus surgery with miR-141/200c manipulation by NPs IA injection. Mass spectrometry analysis, molecular docking and molecular dynamics simulations were performed to investigate the interaction between aptamer and receptor.Results Increased retention of NPs inside joint space is observed. The NPs are freely and deeply penetrant to mice and human cartilage, and unexpectedly persist in chondrocytes for at least 5 weeks. OA chondrocytes microenviroment improves endo/lysosomal escape of microRNAs (miRNAs). Therapeutically, IA injection of miR-141/200c inhibitors provides strong chondroprotection, whereas ectopic expression of miR-141/200c exacerbates OA. Mechanistically, miR-141/200c promotes OA by targeting SIRT1, which acetylates histone in the promoters of interleukin 6 (IL-6), thereby activating IL-6/STAT3 pathway.Conclusions Our findings indicate that this nanocarrier can optimise the transport kinetics of miR-141/200c into chondrocytes, fostering miRNA-specific disease-modifying OA drugs development.