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₉ Integrin and Its Ligands Constitute Critical Joint Microenvironments for Development of Autoimmune Arthritis¹

Masashi Kanayama^2,*, Daisuke Kurotaki^2,*, Junko Morimoto^*, Tsuyoshi Asano^*,, Yutaka Matsui, Yosuke Nakayama^*, Yoshinari Saito^*, Koyu Ito^*, Chiemi Kimura^*, Norimasa Iwasaki, Koji Suzuki^¶, Tanenobu Harada, Hong Mei Li, Jun Uehara, Tadaaki Miyazaki, Akio Minami, Shigeyuki Kon^* and Toshimitsu Uede^3,*

^* Division of Molecular Immunology and Department of Matrix Medicine, Institute for Genetic Medicine, Department of Orthopaedic Surgery, Graduate School of Medicine, and Department of Bioresources, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan; and ^¶ Hokkaido Orthopedic Memorial Hospital, Sapporo, Japan

Osteopontin is critically involved in rheumatoid arthritis; however, the molecular cross-talk between osteopontin and joint cell components that leads to the inflammatory joint destruction is largely unknown. We found that not only osteopontin but also tenascin-C and their common receptor, ₉ integrin, are expressed at arthritic joints. The local production of osteopontin and tenascin-C is mainly due to synovial fibroblasts and, to a lesser extent, synovial macrophages. Synovial fibroblasts and macrophages express ₉ integrin, and autocrine and paracrine interactions of ₉ integrin on synovial fibroblasts and macrophages and its ligands contribute differently to the production of proinflammatory cytokines and chemokines. ₉ integrin is also involved in the recruitment and accumulation of inflammatory cells. Inhibition of ₉ integrin function with an anti-₉ integrin Ab significantly reduces the production of arthrogenic cytokines and chemokines and ameliorates ongoing arthritis. Thus, we identified ₉ integrin as a critical intrinsic regulator that controls the development of autoimmune arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Ministry of Education, Culture, Sports, Science, and Technology of Japan Grant 1620914 (to T.U.).

² M.K. and D.K. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Toshimitsu Uede, Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Kina-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. E-mail address: toshi{at}igm.hokudai.ac.jp

⁴ Abbreviations used in this paper: RA, rheumatoid arthritis; CAIA, collagen Ab-induced arthritis; CHO, Chinese hamster ovary; ECM, extracellular matrix; MMP, matrix metalloproteinase; NHG, normal hamster IgG; OPN, osteopontin; nOPN, N-terminal half of OPN; SMA, smooth muscle actin; TN-C, tenascin-C; TRAP, tartrate-resistant acid phosphatase.

⁵ The online version of this article contains supplemental material.

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The JI 2009 182: 7329-7330. [Full Text]