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The Effect of Apoptosis Signal-Regulating Kinase 1 Gene Transfer on Rat Collagen Induced Arthritis
RYU TERAUCHI, YUJI ARAI, KENJI A. TAKAHASHI, ATSUO INOUE, HITOSHI TONOMURA, HIDETSUGU ASADA, TSUNAO KISHIDA, JIRO IMANISHI, OSAM MAZDA, ISAO KITAJIMA, and TOSHIKAZU KUBO
ABSTRACT. Methods. An adenovirus vector was constructed so that a constitutively active form of ASK1 gene (ASK1ΔN) was expressed in the presence of the Cre recombinase. The ASK1ΔN and Cre adenovirus vectors were cotransduced into cultured synoviocytes derived from patients with rheumatoid arthritis (RA), and apoptosis was evaluated by TUNEL and Hoechst staining. Collagen induced arthritis (CIA) was induced in 8-week-old male DA rats, and 10 days later the 2 adenovirus vectors were coadministered into the ankle joints of the animals. As indicators of severity of arthritis, swelling of the ankle and articular index (AI) scores were evaluated, while histopathological observation of articular tissue was also performed. Results. In the cultured human RA synoviocytes, overexpression of the ASK1ΔN significantly reduced cell viability and induced apoptosis. In the CIA rats transduced with the ASK1ΔN gene, arthritis was significantly promoted in terms of the swelling of the ankle joints and elevation of the AI scores. Histopathological observation also revealed that the constitutively active ASK1 induced massive infiltration of inflammatory cells into the synovial membrane as well as proliferation of synovial fibroblasts. Degeneration of the synovial membrane was not evident. Conclusion. Adenoviral transduction of ASK1ΔN induced apoptosis in RA synoviocytes in vitro, but not in CIA synovium in vivo. (J Rheumatol 2005;32:2373-80) Key Indexing Terms:
ARTHRITIS
From the Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto; Department of Microbiology, Kyoto Prefectural University of Medicine, Kyoto; and Department of Clinical Laboratory Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan. Supported by a Grant-in-Aid for Scientific Research (No.14370472) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. R. Terauchi, MD, PhD; Y. Arai, MD, PhD; K.A. Takahashi, MD, PhD; A. Inoue, MD; H. Tonomura, MD; T. Kubo, MD, PhD, Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine; H. Asada, PhD; J. Imanishi, MD, PhD; O. Mazda, MD, PhD, Department of Microbiology, Kyoto Prefectural University of Medicine; T. Kishida, PhD, Department of Microbiology, Kyoto Prefectural University of Medicine and Louis Pasteur Center for Medical Research; I. Kitajima, MD, PhD, Department of Clinical Laboratory Medicine, Toyama Medical and Pharmaceutical University. Address reprint requests to Dr. K.A. Takahashi, Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: t-keji@mbox.kyoto-inet.or.jp Accepted for publication July 11, 2005. |