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学科主题: 临床医学
题名:
Intra-articular delivery of anti-Hif-2 alpha siRNA by chondrocyte-homing nanoparticles to prevent cartilage degeneration in arthritic mice
作者: Pi, Y.; Zhang, X.; Shao, Z.; Zhao, F.; Hu, X.; Ao, Y.
刊名: GENE THERAPY
发表日期: 2015-06-01
DOI: 10.1038/gt.2015.16
卷: 22, 期:6, 页:439-448
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Biotechnology & Applied Microbiology ; Genetics & Heredity ; Medicine, Research & Experimental
研究领域[WOS]: Biochemistry & Molecular Biology ; Biotechnology & Applied Microbiology ; Genetics & Heredity ; Research & Experimental Medicine
关键词[WOS]: COLLAGEN-INDUCED ARTHRITIS ; HYPOXIA-INDUCIBLE FACTOR-2-ALPHA ; MATRIX-METALLOPROTEINASE 13 ; GENE-THERAPY ; OSTEOARTHRITIC CARTILAGE ; MEDIATED DELIVERY ; TARGETED DELIVERY ; NONVIRAL VECTORS ; RESPONSES ; MODEL
英文摘要:

Hypoxia-inducible factor-2 alpha (Hif-2 alpha) is a potential therapeutic target for osteoarthritis (OA), but the application of this target in the delivery of therapeutic agents to chondrocytes remains a challenge. A chondrocyte-targeting vector was constructed in a previous study to enhance transfection efficiency and specificity of chondrocytes in vivo. This study used vectors to deliver small-interfering RNA (siRNA) and silenced Hif-2 alpha expression to prevent cartilage degeneration in OA-affected mice. After siRNA transfection was conducted by cartilage-targeting nanoparticles, the protein levels of Hif-2 alpha, matrix metalloproteinases (MMP-13, -9), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4, -5), vascular endothelial growth factor (VEGF), type X collagen and nuclear factor (NF)-kappa B in interleukin-1-beta (IL-1 beta)-stimulated chondrocytes were determined. Chondrocyte-targeting ability was also determined by fluorescein isothiocyanate (FITC)-labeled siRNA tracking under a confocal microscope. OA model was established by surgically destabilizing the knee joints of a mouse. Hif-2 alpha siRNA was then delivered intra-articularly with nanoparticles in vivo. Cartilage degeneration and synovium inflammation in the knee joints were analyzed by histomorphometry. IL-1 beta levels in the synovial fluid were also measured by enzyme-linked immunosorbent assay. In vitro assay results showed that catabolic factors, including Hif-2 alpha, MMP-13 and -9, ADAMTS-4, VEGF, collagen type X and NF-kappa B, were downregulated after Hif-2 alpha siRNA transfection by chondrocyte-targeting nanoparticles. In vivo assay results with FITC-labeled siRNA tracking also confirmed that nanoparticles promoted the local concentration and prolonged the retention time of siRNA in the cartilage. Histological analysis results confirmed that nanoparticle-mediated siRNA maintained cartilage integrity and alleviated synovium inflammation. IL-1 beta levels decreased after siRNA was silenced by nanoparticles. Thus, chondrocyte-targeting nanoparticles could deliver Hif-2a siRNA to cartilage and specifically inhibit the expression of catabolic proteins.

语种: 英语
所属项目编号: 81071474/H0605 ; 81301539/H0605
项目资助者: National Natural Science Foundation of China
WOS记录号: WOS:000355880800001
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59021
Appears in Collections:北京大学第三临床医学院_运动医学研究所_期刊论文

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作者单位: Peking Univ, Hosp 3, Inst Sports Med, Dept Sports Med,Beijing Key Lab Sports Injury, Beijing 100191, Peoples R China

Recommended Citation:
Pi, Y.,Zhang, X.,Shao, Z.,et al. Intra-articular delivery of anti-Hif-2 alpha siRNA by chondrocyte-homing nanoparticles to prevent cartilage degeneration in arthritic mice[J]. GENE THERAPY,2015,22(6):439-448.
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