The novel therapeutic roles of TAK1 inhibition in rheumatoid arthritis
| Project/Area Number |
19K21382
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| Project/Area Number (Other) |
18H06294 (2018)
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund (2019)
Single-year Grants (2018) |
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| Review Section |
0907:Oral science and related fields
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| Research Institution | The University of Tokushima |
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Principal Investigator |
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| Project Period (FY) |
2018-08-24 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 炎症性疾患 / TAK1 / 破骨細胞 / 関節リウマチ / NLRP3インフラマソーム / 炎症 / 骨破壊 / TAK1阻害 / インフラマソーム形成 |
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| Outline of Research at the Start |
関節リウマチの治療においては近年様々な生物学的製剤の臨床応用が進んでおり、治療成績は向上している。しかし、依然として炎症の制御が困難で重篤な骨破壊が生じる場合もあり、新たな治療戦略の登場が期待されている。本研究では、種々の炎症性シグナル伝達に重要な役割を担っているセリンスレオニンキナーゼであるTAK1の関節リウマチにおける役割を明らかにし、炎症と骨破壊双方を抑制できる新規治療法の開発を目的とする。
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| Outline of Final Research Achievements |
TGF-β activated kinase-1 (TAK1) was phosphorylated in synovial cells and osteoclasts in CIA mouse which are generally accepted as a RA animal mode. TAK1 inhibitor, LLZ 1640-2 improved arthritis severity and the incidence of arthritis as well as bone destruction in CIA mouse. In addition, IL-1β secretion in sera were upregulated in CIA mice, however LLZ reduced IL-1β levels in sera of CIA mice.
Addition of IL-1β induced RANKL mRNA expression in synovial fibroblasts isolated from CIA mice, and the synovial fibroblasts were able to induce osteoclastogenesis from pre-osteoclasts in the presence of IL-1β. However, LLZ suppressed RANKL expression and the enhancement of osteoclastogenesis by synovial fibroblasts. Moreover, LLZ inhibited RANKL induced osteoclast differentiation.
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| Academic Significance and Societal Importance of the Research Achievements |
慢性関節リウマチ（RA）は、近年様々な生物学的製剤が臨床応用され治療成績は向上しているものの、依然として2～3割の症例では寛解せず、過剰な炎症反応と骨・軟骨破壊が著しい疼痛や運動障害を惹起し、ADLやQOLを著しく低下させる。RA病変部においては滑膜細胞や免疫系細胞による炎症と破骨細胞による骨破壊が起こっており、炎症と骨破壊を制御する新規標的分子の探索とその分子を標的とした治療法の開発が急務である。本研究によってTAK1がRAの炎症と骨破壊の双方を効率的に抑制し得ることが示唆され、本研究結果は今後のRAの新規治療法開発に寄与できるものと考えられる。
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Report
(3 results)
Research Products
(8 results)
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[Journal Article] Persistent activation of calcium-sensing receptor suppresses bone turnover, increases microcracks and decreases bone strength2019
Author(s)
Bingzi Dong, Itsuro Endo, Yukiyo Ohnishi, Yukari Mitsui, Kiyoe Kurahashi, Mai Kanai, Masahiro Hiasa, Jumpei Teramachi, Hirofumi Tenshin, Seiji Fukumoto, Masahiro Abe, Toshio Matsumoto.
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Journal Title
JBMR Plus
Volume: inpress
Issue: 7
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] NLRP3 inflammasome-mediated inflammation and osteoclastic bone resorption in rheumatoid arthritis: the therapeutic roles of TAK1 inhibition.2019
Author(s)
Tenshin H, Teramachi J, Hiasa M, Oda A, Tanimoto K, Shimizu S, Mohannad A, Harada T, Tanaka E, Matsumoto T, Abe M
Organizer
16th Meeting of Bone Biology Forum
Related Report
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[Presentation] TAK1 inhibition effectively alleviates joint inflammation as well as bone destruction in rheumatoid arthritis: Suppression of NLRP3 inflammasome-mediated inflammation and osteoclastic bone resorption.2019
Author(s)
Tenshin H, Teramachi J, Hiasa M, Oda A, Mohannad A, Tanimoto K, Iwasa M, Ariunzaya E, Harada T, Endo I, Tanaka E, Matsumoto T, Abe M.
Organizer
ASBMR 2019 Annual Scientific Meeting
Related Report
Int'l Joint Research
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[Presentation] The role of NLRP3 inflammasome activation in joint inflammation and destruction in rheumatoid arthritis: novel therapeutic approaches with TAK1 inhibition.2019
Author(s)
Tenshin H, Teramachi J, Hiasa M, Oda A, Mohannad A, Tanimoto K, Shimizu S, Harada T, Oura M, Sogabe K, Endo I, Tanaka E, Matsumoto T, Abe M
Organizer
29th ANZBMS Annual Scientific Meeting
Related Report
Int'l Joint Research
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