Cannabinoid Receptor 2 as a potential therapeutic target in Rheumatoid Arthritis

• Project/Area Number: 23591435
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Teikyo University (2013); Tokyo Medical and Dental University (2011-2012)
• Principal Investigator: NANKI Toshihiro 帝京大学, 医学部, 准教授 (00282749)
• Co-Investigator(Kenkyū-buntansha): MIYASAKA Nobuyuki 東京医科歯科大学, 名誉教授 (30157622)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 関節リウマチ / カンナビノイド

Research Abstract

In this study, we investigated therapeutic effects of a selective cannabinoid receptor 2 (CB2) agonist on arthritis. Immunohistochemistry showed that CB2 was expressed on macrophages, fibroblast-like synoviocytes (FLS) and lymphocytes in the synovial tissues from rheumatoid arthritis (RA). JWH133, a selective CB2 agonist, inhibited IL-6, MMP-3 and CCL2 production from TNF-stimulated FLS, and osteoclastogenesis of peripheral blood monocytes. Administration of JWH133 to murine collagen type II (CII)-induced arthritis (CIA) reduced the arthritis score, inflammatory cell infiltration, bone destruction, and anti-CII IgG1 production. The results suggested that a selective CB2 agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, osteoclastogenesis, and autoantibody production.

Research Products

• [Journal Article] Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis (2013)
  • Author(s): Miyabe Y, Miyabe C, Iwai Y, Takayasu A, Fukuda S, Yokoyama W, Nagai J, Jona M, Tokuhara Y, Ohkawa R, Albers HM, Ovaa H, Aoki J, Chun J, Yatomi Y, Ueda H, Miyasaka M, Miyasaka N, Nanki T
  • Journal Title: Arthritis Rheum Volume: 65 Issue: 8 Pages: 2037-2047
  • DOI: 10.1002/art.37991
  • Peer Reviewed
• [Journal Article] CCL18 activates fibroblast-like synoviocytes in patients with rheumatoid arthritis (2013)
  • Author(s): Takayasu A, Miyabe Y, Yokoyama W, Kaneko K, Miyabe C, Fukuda S, Kubota T, Miyasaka N, Nanki T
  • Journal Title: J. Rheumatol Volume: 40 Issue: 6 Pages: 1026-1028
  • DOI: 10.3899/jrheum.121412
  • Peer Reviewed
• [Journal Article] Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections (2013)
  • Author(s): Nanki T, Onoue I, Nagasaka K, Takayasu A, Ebisawa M, Hosoya T, Shirai T, Sugihara T, Hirata S, Kubota T, Harigai M, Miyasaka N
  • Journal Title: Ann. Rheum. Dis Volume: 72 Issue: 6 Pages: 1100-1102
  • DOI: 10.1136/annrheumdis-2012-202768
  • Peer Reviewed
• [Journal Article] CXCR7 agonists inhibit the function of CXCL12 by down-regulation of CXCR4. (2013)
  • Author(s): Uto-Konomi A, McKibben B, Wirtz J, Sato Y, Takano A, Nanki T, Suzuki S
  • Journal Title: Biochem Biophys. Res. Commun Volume: 431 Issue: 4 Pages: 772-776
  • DOI: 10.1016/j.bbrc.2013.01.032
  • Peer Reviewed
• [Journal Article] Am80, a retinoic acid receptor agonist, ameliorates murine vasculitis through the suppression of neutrophil migration and activation (2013)
  • Author(s): Miyabe C, Miyabe Y, Miura NN, Takahashi K, Terashima Y, Toda E, Honda F, Morio T, Yamagata N, Ohno N, Shudo K, Suzuki J, Isobe M, Matsushima K, Tsuboi R, Miyasaka N, Nanki T
  • Journal Title: Arthritis Rheum Volume: 65 Issue: 2 Pages: 503-512
  • DOI: 10.1002/art.37784
  • Peer Reviewed
• [Journal Article] Serum level of soluble CX3CL1/fractalkine is elevated in patients with polymyositis and dermatomyositis, which is correlated with disease activity (2012)
  • Author(s): Suzuki F, Kubota T, Miyazaki Y, Ishikawa K, Ebisawa M, Hirohata S, Ogura T, Mizusawa H, Imai T, Miyasaka N, Nanki T
  • Journal Title: Arthritis Res. Ther Volume: 14 Issue: 2
  • DOI: 10.1186/ar3761
  • Peer Reviewed
• [Journal Article] Arthritic joint-targeting small interfering RNA-encapsulated liposome : Implication for treatment strategy for rheumatoid arthritis (2012)
  • Author(s): Komano Y, Yagi N, Onoue I, Kaneko K, Miyasaka N, Nanki T
  • Journal Title: J. Pharmacol. Exp. Ther Volume: 340 Issue: 1 Pages: 109-113
  • DOI: 10.1124/jpet.111.185884
  • Peer Reviewed
• [Journal Article] Chemerin activates fibroblast-like synoviocytes in patients with rheumatoid arthritis (2011)
  • Author(s): Kayoko Kaneko, et al
  • Journal Title: Arthritis Res Ther Volume: 13 Issue: 5
  • DOI: 10.1186/ar3475
  • Peer Reviewed
• [Presentation] Leucine-rich alpha-2 glycoprotein is a potential disease acitivity marker under IL-6 suppression in autoimmune arthritis (2013)
  • Author(s): Honda H, Serada S, Fujimoto M, Hattori K, Ogata A, Nanki T, Takeuchi T, Naka T
  • Organizer: ヨーロッパリウマチ学会
  • Place of Presentation: マドリード
• [Presentation] Lysophosphatidic acid receptor LPA_1 is essential for development of arthritis (2013)
  • Author(s): Miyabe Y, Miyabe C, Iwai Y, Takayasu A, Fukuda S, Yokoyama W, Nagai J, Jona M, Tokuhara Y, Ohkawa R, Albers HM, Ovaa H, Aoki J, Chun J, Yatomi Y, Ueda H, Miyasaka M, Miyasaka N, Nanki T
  • Organizer: ヨーロッパリウマチ学会
  • Place of Presentation: マドリード
• [Presentation] リゾフォスファチジン酸受容体1(LPA_1)欠損による関節炎抑制 (2013)
  • Author(s): 宮部斉重、宮部千恵、福田真、横山和佳、宮坂信之、南木敏宏
  • Organizer: 第57回日本リウマチ学会総会
  • Place of Presentation: 京都
• [Presentation] Am80, a retinoic acid receptor agonist, ameliorates murine vasculitis through the suppression of neutrophil migration and activation (2012)
  • Author(s): Miyabe C, Miyabe Y, Miura N, Takahashi K, Terashima Y, Toda E, Honda F, Morio T, Yamagata N, Ohno N, Shudo K, Suzuki J, Isobe M, Matsushima K, Tsuboi R, Miyasaka N, Nanki T
  • Organizer: 第76回アメリカリウマチ学会
  • Place of Presentation: ワシントンDC
• [Presentation] Anti-IL-6 autoantibody inhibited elevation of serum C-reactive protein level in two patients with severe bacterial infection (2012)
  • Author(s): Nanki T, Onoue I, Nagasaka K, Hirata S, Hosoya T, Ebisawa M, Sugihara T, Harigai M, Miyasaka N
  • Organizer: ヨーロッパリウマチ学会
  • Place of Presentation: ベルリン
• [Presentation] Am80によるCandida albicans water-soluble fraction誘導血管炎の抑制効果 (2012)
  • Author(s): 宮部千恵、宮部斉重、大野尚仁、高橋啓、宮坂信之、南木敏宏
  • Organizer: 第56回日本リウマチ学会総会
  • Place of Presentation: 東京
• [Presentation] カンナビノイドによる関節炎抑制作用 (2012)
  • Author(s): 福田真、高安愛子、横山和佳、宮部千恵、宮部斉重、宮坂信之、南木敏宏
  • Organizer: 第56回日本リウマチ学会総会
  • Place of Presentation: 東京
• [Presentation] オートタキシン/リゾフォスファチジン酸受容体を標的とした関節リウマチの新規治療法開発 (2012)
  • Author(s): 宮部斉重、宮部千恵、高安愛子、福田真、横山和佳、宮坂信之、南木敏宏
  • Organizer: 第56回日本リウマチ学会総会
  • Place of Presentation: 東京
• [Presentation] 関節リウマチの病態形成におけるCCL25/CCR9相互作用の関与 (2012)
  • Author(s): 横山和佳、金子佳代子、高安愛子、福田真、宮部斉重、宮部千恵、宮坂信之、南木敏宏
  • Organizer: 第56回日本リウマチ学会総会
  • Place of Presentation: 東京
• [Presentation] CCL18による関節リウマチ線維芽細胞様滑膜細胞の活性化 (2012)
  • Author(s): 髙安愛子、宮部斉重、金子佳代子、宮部千恵、横山和佳、福田真、窪田哲朗、宮坂信之、南木敏宏
  • Organizer: 第56回日本リウマチ学会総会
  • Place of Presentation: 東京
• [Presentation] Am80 ameliorates murine model of vasculitis via suppression of neutrophil and endothelial cell activation (2012)
  • Author(s): Miyabe C, Miyabe Y, Miura NN, Takahashi K, Terashima Y, Morio T, Ohno N, Shudo K, Yamagata N, Suzuki K, Suzuki J, Matsushima K, Tsuboi R, Miyasaka N, Nanki T
  • Organizer: The Asia Pacific Meeting of Vasculitis and ANCA Workshop
  • Place of Presentation: 東京
• [Presentation] Autotaxin and Lysophosphatidic Acid Receptors : Potential Target Molecules in New Therapies for Rheumatoid Arthritis (2012)
  • Author(s): Miyabe Y, Miyabe C, Iwai Y, Ebisawa M, Miyasaka M, Miyasaka N, Nanki T
  • Organizer: Keystone Symposia, Chemokines and Leukocyte Trafficking in Homeostasis and Inflammation
  • Place of Presentation: Breckenridge, USA
• [Presentation] 合成レチノイドAm80はCandida albicans water-soluble fraction誘導血管炎を抑制する (2011)
  • Author(s): 宮部千恵、宮部斉重、三浦典子、高橋啓、寺島裕也、大野尚仁、森尾友宏、松島綱治、宮坂信之、南木敏宏
  • Organizer: 第40回日本免疫学会総会
  • Place of Presentation: 千葉
• [Presentation] オートタキシン、リゾフォスファチジン酸受容体を標的とした関節リウマチの新規治療法開発 (2011)
  • Author(s): 宮部斉重、宮部千恵、岩井佳子、海老澤昌史、宮坂昌之、宮坂信之、南木敏宏
  • Organizer: 第40回日本免疫学会総会
  • Place of Presentation: 千葉
• [Presentation] Chemerin Activates Fibroblast-like Synoviocytes in Patients with Rheumatoid Arthritis (2011)
  • Author(s): Kaneko K, Miyabe Y, Takayasu A, Fukuda S, Miyabe C, Ebisawa M, Yokoyama W, Watanabe K, Imai T, Muramoto K, Terashima Y, Sugihara T, Matsushima K, Miyasaka N, Nanki T
  • Organizer: 第75回アメリカリウマチ学会
  • Place of Presentation: シカゴ
• [Presentation] リゾフォスファチジン酸を標的とした関節リウマチの新規治療法開発 (2011)
  • Author(s): 宮部斉重、福田真、金子佳代子、宮坂信之、南木敏宏
  • Organizer: 第55回日本リウマチ学会総会
  • Place of Presentation: 神戸
• [Presentation] カンナビノイドによる関節炎抑制作用
  • Author(s): 福田真、高安愛子、横山和佳、宮部千恵、宮部斉重、宮坂信之、南木敏宏
  • Organizer: 日本リウマチ学会総会
  • Place of Presentation: 東京
• [Book] Retinoic Acid and Immunity. Vitamin-Binding Proteins - Functional Consequences. Ed. Krishnamurti Dakshinamurti and Shyamala Dakshinamurti (2013)
  • Author(s): Yoshishige Miyabe, Chie Miyabe, Toshihiro Nanki
  • Publisher: CRC Press/Taylor & Francis Group