title: Comparison of anti-rheumatic effects of local RNAi-based therapy in collagen induced arthritis rats using various cytokine genes as molecular targets.
abstract: RNA interference (RNAi) provides a powerful means of sequence-specific gene silencing. Several studies show that RNAi may provide promising strategies to treat human diseases by suppressing disease responsible genes in vivo. In locomotor diseases, the progression of collagen-induced arthritis (CIA) is suppressed by tumor necrosis factor-alpha (TNF-alpha)-specific small interfering RNA (siRNA) delivered into the joint. The aim of this study, is to compare the effects of intraarticularly administered siRNAs targeting TNF-alpha, interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and receptor activator of NF-kappaB ligand (RANKL) on CIA in rats. We confirmed that the silencing effects of siRNA duplexes specific for rat TNF-alpha, IL-1beta, IL-6 and RANKL in vitro. Each siRNA was also delivered into the knee joint of CIA rats by the in vivo electroporation method 7, 10, 13 and 16 days after immunization with collagen. Local delivery of TNF-alpha or IL-1beta-specific siRNA ameliorated CIA in rats effectively at the gross morphological, radiographical and histological evaluations. Our results suggested that TNF-alpha and IL-1beta were the cytokines to be targeted in the joint for the treatment of rheumatoid arthritis. The in vivo siRNA transfection method may be useful for selection of target molecules to be silenced for treatment of joint diseases.
authors.affiliation: Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Inoue
authors.forename: Kenji A
authors.initials: KA
authors.lastname: Takahashi
authors.forename: Osam
authors.initials: O
authors.lastname: Mazda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.forename: Masazumi
authors.initials: M
authors.lastname: Saito
authors.forename: Tsunao
authors.initials: T
authors.lastname: Kishida
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shin-Ya
authors.forename: Toru
authors.initials: T
authors.lastname: Morihara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tonomura
authors.forename: Kei
authors.initials: K
authors.lastname: Sakao
authors.forename: Jiro
authors.initials: J
authors.lastname: Imanishi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kubo
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000473:pathology; D018501:Antirheumatic Agents; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D003094:Collagen; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D005528:Foot / Q000000981:diagnostic imaging; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D011859:Radiography; D051381:Rats; D013582:Synovial Fluid / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
chemical_list: D018501:Antirheumatic Agents; D003094:Collagen; D016207:Cytokines; D053583:Interleukin-1beta; D015850:Interleukin-6; D053245:RANK Ligand; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors