Development of a novel method for suppressing bone destruction targeting only pathological dendritic cell-derived osteoclasts

Research Project

Project/Area Number	18K16164
Research Category	Grant-in-Aid for Early-Career Scientists
Allocation Type	Multi-year Fund
Review Section	Basic Section 54020:Connective tissue disease and allergy-related
Research Institution	University of Occupational and Environmental Health, Japan
Principal Investigator	Narisawa Manabu 産業医科大学, 医学部, 助教 (10553802)
Project Period (FY)	2018-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords	関節リウマチ / 破骨細胞 / 樹状細胞 / CTLA-4Ig / アバタセプト / T細胞 / 分化転換 / 滑膜
Outline of Final Research Achievements	As a cause of destruction of bone and cartilage tissue in rheumatoid arthritis (RA), osteoclasts differentiated from dendritic cells (DC-OC) have been reported in animal experiments, but the details have not been known in humans. DC-OCs had a high bone resorption capacity than conventional monocyte-derived osteoclasts (Mo-OC) and had characteristics of DC that Mo-OCs did not have, stimulating to T cell proliferation. It was possible to inhibit it by CTLA-4Ig which was one of therapeutic agents for RA. In addition, DC-OCs were found only in the synovial membrane of RA in comparison with that of osteoarthritis of the knee. DC-OCs had not only the high bone resorption capacity but also the function of T cell stimulation. For the first time, we clarified that DC-OCs deviated from normal bone metabolism may contribute to both the maintenance of inflammation and joint destruction.
Academic Significance and Societal Importance of the Research Achievements	関節や骨格機能に多大な影響を及ぼす慢性骨破壊性疾患である関節リウマチの骨病変において、破骨細胞が非常に重要な役割を担っている。生理的には単球を前駆細胞として分化・癒合する破骨細胞の中に、未成熟樹状細胞から破骨細胞に分化転換する亜集団を確認し、関節リウマチの病的な増殖滑膜にそのサブセットが存在することを証明した。樹状細胞由来破骨細胞が高い骨吸収能のみならず、樹状細胞に類似した免疫活性化作用も伴うことで病態の増悪に大きく関わっている可能性を初めて示すことができた。今後、この病的な樹状細胞由来破骨細胞を治療ターゲットとすることで、副作用を減らした上で骨・関節破壊を抑制できる可能性も拡がったと考える。