期刊
ACS NANO
卷 15, 期 9, 页码 14475-14491出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.1c04005
关键词
disease modifying osteoarthritis drug; MMP13; osteoarthritis; post-traumatic osteoarthritis; siRNA; nano-in-micro; PLGA
类别
资金
- NCI/NIH Cancer Center Support Grant [2P30 CA068485-14]
- NIH [S10RR027631-01, NIH R01 CA224241, NIH R01 EB019409, NIH T32GM007347]
- DOD [DOD CDMRP OR130302]
- Canadian Natural Sciences and Engineering Research Council (NSERC)
- Rheumatology Research Foundation (RRF)
- VA Merit Award [BX004151]
- National Science Foundation Graduate Research Fellowship Program (NSF GRF) [2016212929]
- European Research Council, under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant Agreement [616695]
- European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant Agreement [754490, 872648]
- Marie Curie Actions (MSCA) [872648] Funding Source: Marie Curie Actions (MSCA)
Prolonged RNA interference of MMP13 as a potential disease-modifying therapy for post-traumatic osteoarthritis, reducing MMP13 expression and joint damage to alleviate pain and maintain function.
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-co-glycolic acid) (PLGA) based microPlates (mu PLs) to formulate siNP-mu PLs that maintained siNPs in the joint significantly longer than delivery of free siNPs. Treatment with siNP-mu PLs against MMP13 (siMMP13-mu PLs) 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-mu PL therapy for PTOA.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据