Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37232, United States.
Vanderbilt University School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, United States.
ACS Nano. 2021 Sep 28;15(9):14475-14491. doi: 10.1021/acsnano.1c04005. Epub 2021 Aug 19.
Post-traumatic osteoarthritis (PTOA) associated with joint injury triggers a degenerative cycle of matrix destruction and inflammatory signaling, leading to pain and loss of function. Here, prolonged RNA interference (RNAi) of matrix metalloproteinase 13 (MMP13) is tested as a PTOA disease modifying therapy. MMP13 is upregulated in PTOA and degrades the key cartilage structural protein type II collagen. Short interfering RNA (siRNA) loaded nanoparticles (siNPs) were encapsulated in shape-defined poly(lactic--glycolic acid) (PLGA) based microPlates (μPLs) to formulate siNP-μPLs that maintained siNPs in the joint significantly longer than delivery of free siNPs. Treatment with siNP-μPLs against MMP13 (siMMP13-μPLs) in a mechanical load-induced mouse model of PTOA maintained potent (65-75%) MMP13 gene expression knockdown and reduced MMP13 protein production in joint tissues throughout a 28-day study. MMP13 silencing reduced PTOA articular cartilage degradation/fibrillation, meniscal deterioration, synovial hyperplasia, osteophytes, and pro-inflammatory gene expression, supporting the therapeutic potential of long-lasting siMMP13-μPL therapy for PTOA.
创伤后骨关节炎（PTOA）与关节损伤有关，会引发基质破坏和炎症信号的退行性循环，导致疼痛和功能丧失。在这里，我们测试了长时间 RNA 干扰（RNAi）基质金属蛋白酶 13（MMP13）作为 PTOA 疾病修饰治疗的效果。MMP13 在 PTOA 中上调，并降解关键的软骨结构蛋白 II 型胶原。装载短干扰 RNA（siRNA）的纳米颗粒（siNPs）被包裹在形状定义的聚乳酸-乙醇酸（PLGA）基微盘（μPLs）中，以形成 siNP-μPLs，与游离 siNPs 相比，该微盘能使 siNPs 在关节中保持更长时间。在机械负荷诱导的 PTOA 小鼠模型中，用针对 MMP13 的 siNP-μPLs 治疗，能在 28 天的研究期间保持强效（65-75%）的 MMP13 基因表达抑制，并降低关节组织中 MMP13 蛋白的产生。MMP13 沉默减少了 PTOA 关节软骨降解/纤维化、半月板恶化、滑膜增生、骨赘和促炎基因表达，支持长效 siMMP13-μPL 治疗 PTOA 的治疗潜力。
