2019 Fiscal Year Final Research Report
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) |
Review Section |
0907:Oral science and related fields
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Research Institution | The University of Tokushima |
Principal Investigator |
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Project Period (FY) |
2018-08-24 – 2020-03-31
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Keywords | 炎症性疾患 / TAK1 / 破骨細胞 |
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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Free Research Field |
骨代謝
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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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