【Acta Biomaterialia】郭蕾/王非发现MicroRNA-224-5p纳米颗粒通过平衡关节稳态治疗骨关节炎

doi: 10.1016/j.actbio.2023.06.010.

作者在这项研究中提供了一种有前景的OA基因治疗范例，即miR-224-5p通过调节软骨ECM代谢、滑膜炎、异常血管生成和软骨下骨硬化来缓解OA恶化。G5-AHP有效地将miR-224-5p递送到细胞中并防止其被降解，从而克服了miR-224-5p在OA局部基因治疗中的主要局限性。体外实验表明，G5-AHP/miR-224-5p纳米颗粒具有抗凋亡、抗新生血管和促进自噬的能力。此外，作者发现在DMM诱导的OA小鼠模型中，关节腔注射G5-AHP/miR-224-5p纳米颗粒可抑制关节间隙变窄、减少软骨下骨硬化和改善滑膜炎，这些结果表明G5-AHP/miR-224-5p纳米颗粒通过靶向关节腔中的多个组织来逆转OA恶化。

MicroRNAs play a crucial role in regulating   cartilage extracellular matrix (ECM) metabolism and are being explored as   potential therapeutic targets for osteoarthritis (OA). The present study   indicated that microRNA-224-5p (miR-224-5p) could balance the homeostasis of   OA via regulating cartilage degradation and synovium inflammatory   simultaneously. Multifunctional polyamidoamine dendrimer with amino acids   used as efficient vector to deliver miR-224-5p. The vector could condense   miR-224-5p into transfected nanoparticles, which showed higher cellular   uptake and transfection efficiency compared to lipofectamine 3000, and also   protected miR-224-5p from RNase degradation. After treatment with the   nanoparticles, the chondrocytes showed an increase in autophagy rate and ECM   anabolic components, as evidenced by the upregulation of autophagy-related   proteins and OA-related anabolic mediators. This led to a corresponding   inhibition of cell apoptosis and ECM catabolic proteases, ultimately   resulting in the alleviation of ECM degradation. In addition, miR-224-5p also   inhibited human umbilical vein endothelial cells angiogenesis and   fibroblast-like synoviocytes inflammatory hyperplasia. Integrating the above   synergistic effects of miR-224-5p in regulating homeostasis, intra-articular   injection of nanoparticles performed outstanding therapeutic effect by   reducing articular space width narrowing, osteophyte formation, subchondral   bone sclerosis and inhibiting synovial hypertrophy and proliferation in the   established mouse OA model. The present study provides a new therapy target   and an efficient intra-articular delivery method for improving OA therapy.

【中文摘要】

microRNAs在调节软骨细胞外基质（ECM）的代谢中起着关键作用，是骨关节炎（OA）的潜在治疗目标。本研究表明，microRNA-224-5p（miR-224-5p）可以通过同时调节软骨降解和滑膜炎症来维持OA的稳态。含氨基酸的多功能聚酰胺树枝状聚合物被用作传递miR-224-5p的有效载体。与lipofectamine 3000相比，这一载体可以将miR-224-5p凝聚成可转染的纳米颗粒，显示出更高的细胞摄取率和转染效率，它还可以保护miR-224-5p免受RNase降解。软骨细胞用miR-224-5p纳米颗粒处理后观察到自噬相关蛋白和OA相关合成介质的上调，表明软骨细胞自噬增加和ECM合成组分增多。该纳米颗粒还抑制了人脐静脉内皮细胞的血管生成和纤维母细胞样滑膜细胞的炎症增生。在采用关节腔注射治疗OA小鼠的模型中，该纳米颗粒通过减少关节间隙变窄，阻碍骨质增生，缓解软骨下骨硬化以及抑制滑膜肥厚和增生，发挥了优良治疗效果。本研究为改善OA提供了一种有效的治疗方法。