Intraarticular overexpression of Smad7 ameliorates experimental arthritis.
Intraarticular overexpression of Smad7 ameliorates experimental arthritis.
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DOI：
10.1038/srep35163
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发表时间：
2016-10-12
影响因子：
4.6
通讯作者：
Wang CR
中科院分区：
文献类型：
--
作者：
Chen SY;Shiau AL;Wu CL;Wang CR
类风湿性关节炎(RA)和克罗恩病(CD)都是自身免疫性疾病，其发病机制相互交叉，如靶器官中肿瘤坏死因子的表达增加。尽管口服Smad7反义寡核苷酸在CD中的临床试验取得了成功，但关节内(I.A.)Smad7在类风湿关节中的表达调控尚未见报道。在本研究中，与CD粘膜的研究结果相反，RA滑膜中pSmad2/3的表达水平较高。对滑膜成纤维细胞的体外实验表明，乙酰化Smad7的高表达与低激活状态相关。在胶原诱导性关节炎(CIA)小鼠中，检测到滑膜中pSmad2/3的大量表达，并在关节炎进展过程中增加了水平。为了证明过表达Smad7作为类风湿关节的治疗策略的概念，ia.在CIA小鼠体内注射携带Smad7的慢病毒载体(LVSmad7)。与其他对照组相比，注射LVSmad7的关节的关节炎和组织学评分较低，滑膜炎症、滑膜增生和软骨和骨的侵蚀较少，IL-17和TNF的表达水平也较低。综上所述，我们证明了慢病毒载体介导的I.A.Smad7的过表达可以改善类风湿关节，这意味着基于Smad7的分子策略在RA中的药理学发展。
Rheumatoid arthritis (RA) and Crohn’s disease (CD) are autoimmune disorders with a crosstalk between their pathogenesis such as increased expression of TNF in the target organs. Despite a successful clinical trial with an oral Smad7 antisense oligonucleotide in CD, intraarticular (i.a.) modulation of Smad7 expression has not been performed in rheumatoid joint yet. In this study, contradictory to the findings in CD mucosa, higher levels of pSmad2/3 were found in RA synovium. In vitro experiments with synovial fibroblasts revealed that higher acetylated Smad7 expression was associated with lower activation status. Abundant expression of synovial pSmad2/3 with increased levels during the progression of arthritis was detected in collagen-induced arthritis (CIA) mice. To prove the concept that overexpressing Smad7 as a therapeutic strategy in rheumatoid joint, the i.a. injection of lentiviral vectors carrying Smad7 (LVSmad7) was carried out in CIA mice. In LVSmad7-injected joints, there were lower arthritis and histological scores with less synovitis, synovial hyperplasia and erosion on cartilage and bone as well as reduced IL-17 and TNF expression levels in comparison with other control groups. In conclusion, we demonstrate that lentiviral vector-mediated i.a. overexpression of Smad7 can ameliorate rheumatoid joint, implicating a pharmacological development of Smad7-based molecular strategy in RA.
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影响因子：
4.6
作者：
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通讯作者：
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