Role of the clock genes in rheumatoid arthritis

• Project/Area Number: 26860751
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kobe University
• Principal Investigator: Yoshida Kohsuke 神戸大学, 保健学研究科, 研究員 (80452499)
• Research Collaborator: HASHIRAMOTO Akira ; HASHIMOTO Teppei ; SHIBANUMA Nao ; NAKAGAWA Natsuko
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 関節リウマチ / 時計遺伝子 / 炎症性サイトカイン / シグナル伝達

Outline of Final Research Achievements

I found a novel mechanism between inflammation and circadian rhythm in rheumatoid synovial cells as follows; ① A pro-inflammatory cytokine, Tumor necrosis factor-alpha (TNF-α) reduced the mRNA expression of a circadian core clock gene, Per2, and induced those of Bmal1. However, TNF-α did not affect the oscillation of Bmal1 gene expression.② Up-regulation of Bmal1 gene, induced by TNF-α, was associated with ROR alpha, an activator of Bmal1 gene expression. ③These results were cancelled by an intracellular calcium chelator, BAPTA-AM but not a calcineurin　inhibitor FK-506, suggesting that TNF-α-induced up-regulation of Bmal1 gene is independent of a transcriptional factor NFAT.

Research Products

• [Journal Article] Circadian rhythm and joint stiffness/destruction in rheumatoid arthritis (2015)
  • Author(s): Kohsuke Yoshida, Teppei Hashimoto, Yoshitada Sakai and Akira Hashiramoto
  • Journal Title: International Journal of Clinical Rheumatology Volume: 10 Issue: 5 Pages: 335-344
  • DOI: 10.2217/ijr.15.35
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Involvement of the circadian rhythm and inflammatory cytokines in the pathogenesis of rheumatoid arthritis. (2014)
  • Author(s): Yoshida K, Hashimoto T, Sakai Y, Hashiramoto A.
  • Journal Title: J Immunol Res. Volume: 2014 Pages: 282495-282495
  • DOI: 10.1155/2014/282495
  • Peer Reviewed / Open Access
• [Presentation] Ca2+イオンによる時計遺伝子発現リズムの制御 (2016)
  • Author(s): 中井綾子、吉田幸祐、橋本哲平、金城健太、橋本尚憲、鈴木行人、川崎善子、立石浩司、中川夏子、柴沼均、立石博臣、柱本照
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-04-22
• [Presentation] カルシウムシグナルを介したTNF-αによる時計遺伝子発現制御 (2015)
  • Author(s): 中井 綾子、吉田 幸祐、橋本 哲平、柴沼 均、 金城 健太、 橋本 尚憲、 柱本 照
  • Organizer: 第59回日本リウマチ学会総会・学術集会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市）
  • Year and Date: 2015-04-23
• [Presentation] TNFα modulates the expression of circadian clock genes via calcium signaling in rheumatoid synovial cells. (2014)
  • Author(s): Kohsuke Yoshida, Nao Shibanuma, Teppei Hashimoto, Yoshiko Kawasaki, Naonori Hashimoto, Ayako Nakai, Kenta Kaneshiro, Koji Tateishi, Natsuko Nakagawa, Akira Hashiramoto
  • Organizer: American college of Rheumatology, 78th Annual Scientific Meeting
  • Place of Presentation: Boston Convention & Exhibition Center（Boston, MA, USA）
  • Year and Date: 2014-11-17