Analysis on the influence of RANKL reverse signaling in the development of rheumatoid arthritis

Research Project

Project/Area Number	26713045
Research Category	Grant-in-Aid for Young Scientists (A)
Allocation Type	Partial Multi-year Fund
Research Field	Orthopaedic surgery
Research Institution	The University of Tokyo
Principal Investigator	Ikebuchi Yuki 東京大学, 医学部附属病院, 助教 (20645725)
Research Collaborator	HONMA Masashi 東京大学, 医学部附属病院, 講師 (60401072)
Project Period (FY)	2014-04-01 – 2018-03-31
Project Status	Completed (Fiscal Year 2017)
Budget Amount *help	¥23,530,000 (Direct Cost: ¥18,100,000、Indirect Cost: ¥5,430,000) Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000) Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000) Fiscal Year 2014: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
Keywords	RANKL / 関節リウマチ / 細胞分化制御 / 骨・軟骨代謝 / 細胞内シグナル伝達 / 細胞内シグナル / RANK-RANKL相互作用
Outline of Final Research Achievements	We revealed that RANKL reverse signaling plays the significant roles in the cycle of bone resorption and formation. RANKL is expressed in chondrocytes, activated T cells, and synovial fibroblasts as well as osteoblasts/osteocytes. In the development of rheumatoid arthritis, the imbalance of these cells differentiation and activities is observed, therefore, we analyzed on the pathological influence of RANKL reverse signaling in each cell line. At first, multimeric anti-RANKL antibody were designed for cross-linking RANKL molecules. In fact, scDb-Fc protein, which was composed of four scFv domains connected with Fc, showed strong potential of RANKL reverse signaling. Using this agonistic moiety, we confirmed the effect of RANKL reverse signaling in each cell line. Furthermore, collagen-induced arthritis model mice were used for evaluating the effects of RANKL reverse signaling in vivo.