Elucidation of pathophysiology and development of new treatments with the neurotransmitter dopamine for rheumatoid arthritis

• Project/Area Number: 19K08926
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: HANAMI KENTARO 産業医科大学, 医学部, 講師 (50441853)
• Co-Investigator(Kenkyū-buntansha): 田中 良哉 産業医科大学, 医学部, 教授 (30248562)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ドパミン受容体シグナル

Outline of Research at the Start

神経系及び神経伝達物質が免疫系のみならず、骨代謝へも影響を与えている事が近年報告されている。我々は、関節リウマチ患者炎症性滑膜の樹状細胞にドパミンが豊富に存在する事、ドパミンD1様受容体阻害薬が滑膜炎症及び関節破壊を抑制しうる事をSCIDマウスを使ったヒト関節リウマチモデルにおける検討で明らかにし、更にはドパミンD2受容体シグナルが細胞内cAMP-c-Fos-NFATc1を抑制する事で 破骨細胞形成を抑制する事を報告しており、神経伝達物質が、関節リウマチの新規治療方法となり得る可能性が考えられる。本研究では、神経伝達物質による関節リ ウマチに対しての新規治療法の開発を目的とする。

Outline of Final Research Achievements

It has been reported that the nervous system and neurotransmitters affect not only the immune system but also bone metabolism. Dopamine, a typical neurotransmitter, revealed that dopamine is abundant in the dendritic cells of the inflammatory synovium of patients with rheumatoid arthritis. Furthermore, it was clarified that the dopamine D2 receptor signal suppresses the formation of osteoclasts by suppressing the intracellular cAMP-c-Fos-NFATc1. Based on these results, we investigated the possibility that neurotransmitters could be a new treatment method for rheumatoid arthritis, and a new treatment method for rheumatoid arthritis with neurotransmitters.

Academic Significance and Societal Importance of the Research Achievements

我々の結果からは、炎症性サイトカイン抑制・骨吸収抑制による影響は考えられ、cAMP応答配列を介したwntシグナル修飾も近年報告されており、ドパミンシグナルによるcAMPを介した骨芽細胞形成への直接的な影響も考えられる。ドパミンシグナルによる骨破壊病態への治療応用を想定した際に、骨代謝に対するメカニズムの解明は必須であり、本研究は新規治療への展開にとどまらず、神経と骨免疫のクロストークを解明するブレークスルーとしての可能性を有するため、医学的にも社会的にも多大な意義を持つものと考える。

Research Products

• [Journal Article] Nailfold microvascular abnormalities are associated with a higher prevalence of pulmonary arterial hypertension in patients with MCTD (2022)
  • Author(s): Todoroki Yasuyuki、Kubo Satoshi、Nakano Kazuhisa、Miyazaki Yusuke、Ueno Masanobu、Satoh-Kanda Yurie、Kanda Ryuichiro、Miyagawa Ippei、Hanami Kentaro、Nakatsuka Keisuke、Saito Kazuyoshi、Nakayamada Shingo、Tanaka Yoshiya
  • Journal Title: Rheumatology Volume: Mar 14:keac165 Issue: 12 Pages: 4875-4884
  • DOI: 10.1093/rheumatology/keac165
  • Peer Reviewed
• [Journal Article] Eosinophilic granulomatosis with polyangiitis exhibits T cell activation and IgG4 immune response in the tissue; comparison with IgG4-related disease (2022)
  • Author(s): Kubo Satoshi、Kanda Ryuichiro、Nawata Aya、Miyazaki Yusuke、Kawabe Akio、Hanami Kentaro、Nakatsuka Keisuke、Saito Kazuyoshi、Nakayamada Shingo、Tanaka Yoshiya
  • Journal Title: RMD Open Volume: 8 Issue: 1 Pages: e002086-e002086
  • DOI: 10.1136/rmdopen-2021-002086
  • Peer Reviewed
• [Journal Article] Efficacy and safety of belimumab during maintenance therapy in patients with systemic lupus erythematosus (2021)
  • Author(s): Miyazaki Yusuke、Nakayamada Shingo、Sonomoto Koshiro、Kawabe Akio、Inoue Yoshino、Okubo Naoaki、Iwata Shigeru、Hanami Kentaro、Tanaka Yoshiya
  • Journal Title: Rheumatology Volume: Dec 28:keab953. Issue: 9 Pages: 3614-3626
  • DOI: 10.1093/rheumatology/keab953
  • Peer Reviewed
• [Journal Article] Efficacy and safety of high-dose of mycophenolate mofetil compared with cyclophosphamide pulse therapy as induction therapy in Japanese patients with proliferative lupus nephritis (2021)
  • Author(s): Ohkubo Naoaki、Iwata Shigeru、Nakano Kazuhisa、Miyagawa Ippei、Hanami Kentaro、Fukuyo Shunsuke、Miyazaki Yusuke、Kawabe Akio、Nakayamada Shingo、Tanaka Yoshiya
  • Journal Title: Modern Rheumatology Volume: - Issue: 6 Pages: 1077-1085
  • DOI: 10.1093/mr/roab113
  • Peer Reviewed / Open Access
• [Journal Article] A case of eosinophilic granulomatosis with polyangiitis as a mimicker of IgG4-related disease (2020)
  • Author(s): Kanda Ryuichiro、Kubo Satoshi、Nakano Kazuhisa、Kawabe Akio、Nawata Aya、Hanami Kentaro、Nakayamada Shingo、Tanaka Yoshiya
  • Journal Title: Modern Rheumatology Case Reports Volume: 4 Issue: 2 Pages: 278-282
  • DOI: 10.1080/24725625.2020.1759200
  • Peer Reviewed
• [Journal Article] The additive effects of hydroxychloroquine to maintenance therapy with standard of care in patients with systemic lupus erythematosus. (2020)
  • Author(s): Miyagawa I, Nakano K, Nakayamada S, Iwata S, Hanami K, Fukuyo S, Kubo S, Kawabe A, Miyazaki Y, Inoue Y, Ueno M, Ohkubo N, Fujita Y, Tanaka Y.
  • Journal Title: Int J Rheum Dis. Volume: 23(4) Issue: 4 Pages: 549-558
  • DOI: 10.1111/1756-185x.13792
  • Peer Reviewed
• [Journal Article] 5-year remission rate after the discontinuation of adalimumab in patients with rheumatoid arthritis: Long-term follow-up results of the HONOR study. (2020)
  • Author(s): Yamaguchi A, Hirata S, Kubo S, Fukuyo S, Hanami K, Nakano K, Nakayamada S, Saito K, Tanaka Y.
  • Journal Title: Mod Rheumatol. Volume: 15 Issue: 5 Pages: 1-8
  • DOI: 10.1080/14397595.2019.1702141
  • Peer Reviewed
• [Journal Article] Clinical aspects in patients with rheumatoid arthritis complicated with lymphoproliferative disorders without regression after methotrexate withdrawal and treatment for arthritis after regression of lymphoproliferative disorders. (2020)
  • Author(s): Nakano K, Saito K, Nawata A, Hanami K, Kubo S, Miyagawa I, Fujino Y, Nakayamada S, Tanaka Y.
  • Journal Title: Mod Rheumatol. Volume: 27 Issue: 1 Pages: 1-7
  • DOI: 10.1080/14397595.2020.1741870
  • Peer Reviewed
• [Book] リウマチ病学テキスト（改訂第3版） (2022)
  • Author(s): 日本リウマチ財団教育研修委員会、日本リウマチ学会生涯教育委員会
  • Total Pages: 608
  • Publisher: 南江堂
  • ISBN: 9784524231584