Disruption of circadian rhythm aggravates experimental arthritis: study in cry gene-knockout mice.

• Project/Area Number: 18591110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kobe University
• Principal Investigator: HASHIRAMOTO Akira Kobe University, FES School of Medicine, Associate Professor (80346246)
• Co-Investigator(Kenkyū-buntansha): MIURA Yasushi Kobe University, FHS School fo Medicine, Associate Professor (60346244)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,810,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2006: ¥2,900,000 (Direct Cost: ¥2,900,000)
• Keywords: circadian rhythum / Cry gene / rheumatoid arthritis / TNF-a / Cry / TNF-a / 関節炎 / 時計遺伝子

Research Abstract

Mammalian clock genes, Per and Cry, physiologically regulate circadian rhythm. We show that experimental arthritis in mice impairs rhythmic expression of Per and Cry, and deletion of Cry further aggravates arthritis to maximal levels. While Wee-1 kinase and c-Fos/ AP-1, a transactivator of Wee-1, are up-regulated in human rheumatoid arthritis (RA), and Wee-1 is the sole molecule up-regulated among cell cycle regulators in Cry-1/2 deficient mice, the splenic T cells of Cry-1/2 deficient mice were activated, and the molecules playing essential roles in arthritis such as c-Fos/AP-1, Wee-1, inflammatory cytokines including TNF-a, IL-lb and IL-6, and matrix-degrading MMP-3 were all increased. In particular, Cry transactivated pro-inflammatory cytokine TNF-a. Thus, biological clock modulates human health and disease, in particular, arthritis

Research Products

• [Journal Article] Easy and Accurate Diagnosis of Rheumatoid Arthritis Using Anti-Cyclic Citrullinated Peptide 2 Antibody, Swollen Joint Count, and C-Reactive Protein/Rheumatoid Factor. (2008)
  • Author(s): Yamane T, Hashiramoto A, Tanaka Y, Tsumiyama K, Miura Y, Shiozawa K, Chihara K, Shiozawa S.
  • Journal Title: J Rheumatol 35 Pages: 414-420
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Easy and Accurate Diagnosis of Rheumatoid Arthritis Using Anti-Cyclic Citrullinated Peptide 2 Antibody, Swollen Joint Count, and C-Reactive Protein/Rheumatoid Factor (2008)
  • Author(s): Yamane, T, Hashiramoto, A, Tanaka, Y, Tsumiyama, K, Miura, Y, Shiozawa, K, Chihara, K, Shiozawa, S
  • Journal Title: J Rheumatol 35(3) Pages: 414-420
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiopoietin 1 directly induces destruction of the rheumatoid joint by cooperative, but independent, signaling via ERK/MAPK and phosphatidylinositol 3-kinase/Akt. (2007)
  • Author(s): Hashiramoto A, Sakai C, Yoshida K, Tsumiyama K, Miura Y, Shiozawa K, Nose M, Komai K, Shiozawa S.
  • Journal Title: Arthritis Rheum. 56 Pages: 2170-2179
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against fas-induced apoptosis. (2007)
  • Author(s): Hayashi S, Miura Y, Nishiyama T, Mitani M, Tateishi K, Sakai Y, Hashiramoto A, Kurosaka M, Shiozawa S, Doita M.
  • Journal Title: Arthritis Rheum. 56 Pages: 1067-1075
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against fas-induced apoptosis (2007)
  • Author(s): Hayashi, S, Miura, Y, Nishiyama, T, Mitani, M, Tateishi, K, Sakai, Y, Hashiramoto, A, Kurosaka, M, Shiozawa, S, Doita, M
  • Journal Title: Arthritis Rheum 56(4) Pages: 1067-1075
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiopoietin 1 directly induces destruction of the rheumatoid joint by cooperative, but independent, signaling via ERK/MAPK and phosphatidylinositol3-kinase/Akt (2007)
  • Author(s): Hashiramoto, A, Sakai, C, Yoshida, K, Tsumiyama, K, Miura, Y, Shiozawa, K, Nose, M, Komai, K, Shiozawa, S
  • Journal Title: Arthritis Rheum 56(7) Pages: 2170-2179
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against fas-induced apoptosis. (2007)
  • Author(s): Hayashi S, Miura Y, Nishiyama T, Mitani M, Tateishi K, Sakai Y, Hashiramoto A, Kurosaka M, Shiozawa S, Doita M
  • Journal Title: Arthritis Rheum 56・1 Pages: 1067-1075
• [Journal Article] Ganglioside GM3promotes cell migration by regulating MAP K and c-Fos/AP-1. (2006)
  • Author(s): Hashiramoto A, Mizukami H, Yamashita T.
  • Journal Title: Oncogene 25 Pages: 3948-55
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. (2006)
  • Author(s): Takami N, Osawa K, Miura Y, Komai K, Taniguchi M, Shiraishi M, Sato K, Iguchi T, Shiozawa K, Hashiramoto A, Shiozawa S.
  • Journal Title: Arthritis Rheum. 54 Pages: 779-87
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Anchorage on fibronectin via VIA-5(a5b1 integrin)protects rheumatoid synovialcells from Fas-induced apoptosis (2006)
  • Author(s): Kitagawa, A, Miura, Y, Saura, R, Mitani, M, Ishikawa, H, Hashiramoto, A, Yoshiya, S, Shiozawa, S, Kurosakam M
  • Journal Title: Ann Rheum Dis 65(6) Pages: 721-7
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ganglioside GM3promotes cell migration by regulating MAPK and c-Fos/AP-1 (2006)
  • Author(s): Hashiramoto, A, Mizukami, H, Yamashita, T
  • Journal Title: Oncogene 25(28) Pages: 3948-55
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells (2006)
  • Author(s): Takami, N, Osawa, K, Miura, Y, Komai, K, Taniguchi, M, Shiraishi, M, Sato, K, Iguchi, T, Shiozawa, K, Hashiramoto, A, Shiozawa, S
  • Journal Title: Arthritis Rheum 54(3) Pages: 779-87
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ganglioside GM3promotes cell migration by regulating MAPK and c-Fos/AP-1. (2006)
  • Author(s): Hashiramoto A, Mizukami H, Yamashita T
  • Journal Title: Oncogene 25・28 Pages: 3948-3955
• [Journal Article] Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. (2006)
  • Author(s): Takami N, Osawa K, Miura Y, Komai K, Taniguchi M, Shiraishi M, Sato K, Iguchi T, Shiozawa K, Hashiramoto A, Shiozawa S
  • Journal Title: Arthritis Rheum. 54・3 Pages: 779-787
• [Presentation] Variant Death Receptor 3 Gene, Genetically Associated with Rheumatoid Arthritis Inhibit TL1A-induced Splenocyte Signaling and CD4/8 Cell Subset in Thymus (2007)
  • Author(s): Kawazoe T, Hashiramoto A, Tsumiyama K, Shiozawa S,
  • Organizer: American College of Rheumatology 71th Annual Scientific Meeting
  • Place of Presentation: Boston
  • Year and Date: 2007-11-06
• [Presentation] RAにおける睡眠障害と関節炎 (2007)
  • Author(s): 柱本照
  • Organizer: 第17回日本リウマチ学会近畿支部学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2007-09-08
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 睡眠障害Cry遺伝子欠損マウスでは実験的関節炎が増悪する (2006)
  • Author(s): 山根隆志、柱本照、積山賢、塩沢俊一
  • Organizer: 第50回日本リウマチ学会学術総会
  • Place of Presentation: 長崎
  • Year and Date: 2006-04-25
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Disruption of circadian rhythm aggravates experimental arthritis:study in cry gene-knockout mice. (2006)
  • Author(s): Yamane T, Hashiramoto A, Tsumiyama K, Okamura H, Shiozawa S.
  • Organizer: American College of Rheumatology 70th Annual Scientific Meeting
  • Place of Presentation: Washington, DC
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Mutant type human death receptor 3 acts on the onset of collagen-induced arthritis. (2006)
  • Author(s): Hashiramoto A, Tanaka K, Nagahama T, Miura Y, Shiozawa S.
  • Organizer: American College of Rheumatology 70th Annual Scientific Meeting
  • Place of Presentation: Washington, DC
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Anti-CCP2 assay accurately predicts future development of rheumatoid arthritis as early as 3 months from onset of arthritic symptoms. (2006)
  • Author(s): Yamane T, Shiozawa K, Hashiramoto A, Tanaka Y, Tsumiyama K, Miura Y, Shiozawa S.
  • Organizer: American College of Rheumatology 70th Annual Scientific Meeting
  • Place of Presentation: Washington, DC
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Once-anergized T cell in autoimmune-prone MRL/1pr mice cannot be reactivated from anergy and generate autoantibodies after repeated priming with exogenous antigen. (2006)
  • Author(s): Tsumiyama K, Isaka S, Hashiramoto A, Shiozawa S.
  • Organizer: American College of Rheumatology 70th Annual Scientific Meeting
  • Place of Presentation: Washington, DC
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] A novel small molecule AP-1 inhibitor T-5224 resolves mouse type II collagen-induced arthritis in a c-Fos/AP-1-specific fashion. (2006)
  • Author(s): Aikawa Y, Morimoto K, Yamamoto T, Chaki H, Hashiramoto A, Narita H, Hirono S, Shiozawa S.
  • Organizer: American College of Rheumatology 70th Annual Scientific Meeting
  • Place of Presentation: Washington, DC
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Therapeutic efficacy of a novel small molecule AP-l inhibitor T-5224 on collagen-induced arthritis in mice: characterization of anti-arthritic effect directly inhibiting IL-1β and matrix degrading MMPs. (2006)
  • Author(s): Morimoto K, Aikawa Y, Yamamoto T, Chaki H, Hshiramoto A, Narita H, Hirono S, Shiozawa S.
  • Organizer: American College of Rheumatology 70th Annual Scientific Meeting
  • Place of Presentation: Washington, DC
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] RA疾患遺伝子感受性候補ANG-1の機能 (2006)
  • Author(s): 柱本 照
  • Organizer: 第51回日本リウマチ学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 新規低分子c-FOS/AP-1阻害剤T-5224のマウスII型コラーゲン誘発関節炎(CIA)に対する予防効果 (2006)
  • Author(s): 塩沢俊一、柱本照、相川幸彦、広野修一
  • Organizer: 第51回日本リウマチ学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 新規低分子c-FOS/AP-1阻害剤T-5224の治療的投与によるマウスII型コラーゲン誘発関節炎(CIA)の抑制 (2006)
  • Author(s): 塩沢俊一、柱本照、相川幸彦、広野修一
  • Organizer: 第51回日本リウマチ学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 関節炎と概日リズム-時計遺伝子欠損マウスで実験的関節炎は増悪する (2006)
  • Author(s): 山根隆志、柱本照、積山賢、塩沢俊一
  • Organizer: 第51回日本リウマチ学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 関節リウマチ疾患遺伝子変異型dr3 ドランスジェニックマウス脾細胞ではNFkB活性化が抑制される (2006)
  • Author(s): 川添高子、柱本照、三浦靖史、塩沢俊一
  • Organizer: 第51回日本リウマチ学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Heat Schock Protein90はインテグリンを介して関節リウマチ滑膜細胞のシグナル伝達に作用する (2006)
  • Author(s): 柱本照、川添高子、吉田幸祐、阿部修治、中川夏子、三枝康宏、塩沢和子、石川斎、塩沢俊一
  • Organizer: 第51回日本リウマチ学会学術総会
  • Place of Presentation: 横浜
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Disruption of circadian rhythm aggravates experimental arthritis: study in cry gene-knockout mice (2006)
  • Author(s): Yamane, T, Hashiramoto, A, Tsumiyama, K, Okamum, H, Shiozawa, S
  • Organizer: American College of Rheumatology 70th Annual Scientific Meeting
  • Place of Presentation: Washington, DC
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Mutant type human death receptor 3 acts on the onset of collagen-induced arthritis
  • Author(s): Hashiramoto, A, Tanaka, K, Nagahama, T, Miura, Y, Shiozawa, S
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Anti-CCP2 assay accurately predicts future development of rheumatoid arthritis as early as 3 months from onset of arthritic symptoms
  • Author(s): Yamane, T, Shiozawa, K, Hashiramoto, A, Tanaka, Y, Tsumiyama, K, Miura, Y, Shiozawa, S
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A novel small molecule AP-1 inhibitor T-5224 resolves mouse type II collagen-induced arthritis in a c-Fos/AP-1-specific fashion
  • Author(s): Aikawa, Y, Morimoto, K, Yamamoto, T, Chaki, H, Hashiramoto, A, Narita, H, Hirono, S, Shiozawa, S
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Once-anergized T cell in autoimmune-prone MRLIpr mice cannot be reactivated from anergy and generate autoantibodies after repeated priming with exogenous antigen
  • Author(s): Tsumiyama, K, Isaka, S, Hashiramoto, A, Shiozawa, S
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Therapeutic efficacy of a novel small molecule AP-1 inhibitor T-5224 on collagen-induced arthritis in mice: characterization of anti-arthritic effect directly inhibiting IL-1.6 and matrix degrading MMPs
  • Author(s): Morimoto, K, Aikawa, Y, Yamamoto, T,Chaki, H, Hshiramoto, A, Narita, H, Hirono, S, Shiozawa, S
  • Description: 「研究成果報告書概要(欧文)」より