背景:骨关节炎(OA)是一种退行性关节疾病,其特征是关节软骨进行性变性,导致疼痛,刚度,失去关节功能。OA的发病机制涉及多种因素,包括增加的细胞内活性氧(ROS),软骨细胞凋亡增强,和软骨基质代谢紊乱。这些过程有助于细胞外基质(ECM)的分解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一种有希望的方法,包括hATTR和急性肝卟啉症。通过利用自然细胞机制进行基因沉默,RNAi允许特异性抑制与疾病发病机理有关的靶基因。在OA的背景下,靶向关键分子,如基质金属蛋白酶-13(MMP13),在软骨退化中起关键作用,拥有巨大的治疗潜力。
结果:在这项研究中,我们开发了一种用于OA的创新治疗方法,该方法使用脂质体包封的siMMP13和NG-Monomethyl-L-精氨酸乙酸酯(L-NMMA)的组合来形成可注射水凝胶.水凝胶用作siMMP13的递送载体,允许持续释放和靶向递送至受影响的关节。对内侧半月板(DMM)模型小鼠的去稳定化进行的实验证明了该复合水凝胶的治疗功效。水凝胶处理显著抑制软骨基质的降解,组织学分析显示软骨结构保留和蛋白聚糖损失减少。此外,水凝胶有效抑制细胞内ROS在软骨细胞中的积累,表明其抗氧化性能。此外,它减弱了软骨细胞凋亡,如凋亡标志物水平降低所证明的。
结论:总之,含有siMMP13的可注射水凝胶,具有抗ROS和抗凋亡特性,可能是未来骨关节炎的有效治疗策略。
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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.