title: Intraarticular overexpression of Smad7 ameliorates experimental arthritis.
abstract: 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.
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng-Li Road, Tainan, 70428, Taiwan.
authors.forename: Shih-Yao
authors.initials: SY
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, 70101, Taiwan.
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Shiau
authors.affiliation: Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, 70101, Taiwan.
authors.forename: Chao-Liang
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng-Li Road, Tainan, 70428, Taiwan.
authors.forename: Chrong-Reen
authors.initials: CR
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D005822:Genetic Vectors; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D007270:Injections, Intra-Articular; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D020381:Interleukin-17; D011994:Recombinant Proteins; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1