Chen Shih-Yao, Shiau Ai-Li, Wu Chao-Liang, Wang Chrong-Reen
Section of Rheumatology, Department of Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng-Li Road, Tainan, 70428, Taiwan.
Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, 70101, Taiwan.
Sci Rep. 2016 Oct 12;6:35163. doi: 10.1038/srep35163.
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.
类风湿关节炎（RA）和克罗恩病（CD）是自身免疫性疾病，它们在发病机制上存在相互影响，比如靶器官中肿瘤坏死因子（TNF）表达增加。尽管口服Smad7反义寡核苷酸在CD的临床试验中取得了成功，但类风湿关节内尚未进行Smad7表达的调节。在本研究中，与CD黏膜中的发现相反，RA滑膜中发现磷酸化Smad2/3水平更高。对滑膜成纤维细胞进行的体外实验表明，更高的乙酰化Smad7表达与更低的激活状态相关。在胶原诱导的关节炎（CIA）小鼠中检测到，在关节炎进展过程中滑膜pSmad2/3表达丰富且水平升高。为了验证在类风湿关节中过表达Smad7作为一种治疗策略的概念，在CIA小鼠中进行了关节内注射携带Smad7的慢病毒载体（LVSmad7）。与其他对照组相比，在注射LVSmad7的关节中，关节炎和组织学评分更低，滑膜炎、滑膜增生以及软骨和骨侵蚀更少，白细胞介素-17（IL-17）和TNF表达水平也降低。总之，我们证明慢病毒载体介导的关节内Smad7过表达可改善类风湿关节，这意味着基于Smad7的分子策略在RA中有药理学开发前景。
