Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, No. 3, Qingchun Road East, Hangzhou, 310016, P.R. China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, No. 3, Qingchun Road East, Hangzhou, 310016, P.R. China.
J Nanobiotechnology. 2024 Aug 2;22(1):466. doi: 10.1186/s12951-024-02740-w.
Osteoarthritis (OA) is a degenerative joint disease characterized by the progressive degeneration of articular cartilage, leading to pain, stiffness, and loss of joint function. The pathogenesis of OA involves multiple factors, including increased intracellular reactive oxygen species (ROS), enhanced chondrocyte apoptosis, and disturbances in cartilage matrix metabolism. These processes contribute to the breakdown of the extracellular matrix (ECM) and the loss of cartilage integrity, ultimately resulting in joint damage and dysfunction. RNA interference (RNAi) therapy has emerged as a promising approach for the treatment of various diseases, including hATTR and acute hepatic porphyria. By harnessing the natural cellular machinery for gene silencing, RNAi allows for the specific inhibition of target genes involved in disease pathogenesis. In the context of OA, targeting key molecules such as matrix metalloproteinase-13 (MMP13), which plays a critical role in cartilage degradation, holds great therapeutic potential.
In this study, we developed an innovative therapeutic approach for OA using a combination of liposome-encapsulated siMMP13 and NG-Monomethyl-L-arginine Acetate (L-NMMA) to form an injectable hydrogel. The hydrogel served as a delivery vehicle for the siMMP13, allowing for sustained release and targeted delivery to the affected joint. Experiments conducted on destabilization of the medial meniscus (DMM) model mice demonstrated the therapeutic efficacy of this composite hydrogel. Treatment with the hydrogel significantly inhibited the degradation of cartilage matrix, as evidenced by histological analysis showing preserved cartilage structure and reduced loss of proteoglycans. Moreover, the hydrogel effectively suppressed intracellular ROS accumulation in chondrocytes, indicating its anti-oxidative properties. Furthermore, it attenuated chondrocyte apoptosis, as demonstrated by decreased levels of apoptotic markers.
In summary, the injectable hydrogel containing siMMP13, endowed with anti-ROS and anti-apoptotic properties, may represent an effective therapeutic strategy for osteoarthritis in the future.
骨关节炎（OA）是一种退行性关节疾病，其特征为关节软骨进行性退化，导致疼痛、僵硬和关节功能丧失。OA 的发病机制涉及多个因素，包括细胞内活性氧（ROS）增加、软骨细胞凋亡增强以及软骨基质代谢紊乱。这些过程导致细胞外基质（ECM）的破坏和软骨完整性的丧失，最终导致关节损伤和功能障碍。RNA 干扰（RNAi）治疗已成为治疗各种疾病的有前途的方法，包括 hATTR 和急性肝卟啉症。通过利用细胞内基因沉默的天然机制，RNAi 允许特异性抑制参与疾病发病机制的靶基因。在 OA 中，靶向关键分子，如在软骨降解中起关键作用的基质金属蛋白酶-13（MMP13），具有很大的治疗潜力。
在这项研究中，我们开发了一种使用脂质体包裹的 siMMP13 和 NG-单甲基-L-精氨酸乙酸盐（L-NMMA）形成可注射水凝胶的 OA 治疗新方法。水凝胶作为 siMMP13 的递送载体，允许其持续释放并靶向递送到受影响的关节。对内侧半月板不稳定（DMM）模型小鼠的实验表明了这种复合水凝胶的治疗效果。水凝胶治疗显著抑制了软骨基质的降解，组织学分析显示保留了软骨结构并减少了糖胺聚糖的丢失。此外，水凝胶有效地抑制了软骨细胞内 ROS 的积累，表明其具有抗氧化特性。此外，它还减轻了软骨细胞凋亡，表现为凋亡标志物水平降低。
综上所述，具有抗 ROS 和抗凋亡特性的含 siMMP13 的可注射水凝胶可能代表未来治疗骨关节炎的有效治疗策略。
