| Project/Area Number |
13557041
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
内科学一般
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| Research Institution | St.Marianna University School of Medicine |
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Principal Investigator |
OZAKI Shoichi St.Marianna Univ, Sch Med, Professor, 医学部, 教授 (00231233)
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| Co-Investigator(Kenkyū-buntansha) |
SUGIO Hiromu The Univ of Tokushima, Institute for Genome Research, Professor, 分子酵素学研究センター, 教授 (50211305)
OGAWA Yoshihiro Tokyo Medical and Dental Univ Medical Research Institute, Professor, 難治疾患研究所, 教授 (70291424)
TANAKA Masao Kyoto Univ, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (10332719)
OOMOTO Yasuichi Otsuka Research Laboratory, Chief Investigator, 医薬第一研究所, 主任研究員
YOSHIZAKI Kazuyuki Osaka Univ, Sch of Health and Sport Sciences, Professor, 健康体育部, 教授 (90144485)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥15,900,000 (Direct Cost: ¥15,900,000)
Fiscal Year 2003: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Keywords | folistatin-related protein / FRP / transgenic mouse / synovial cells / TGF-beta / MMP1 / anti-type II collagen antibody / c-fos / ノックアウトマウス |
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| Research Abstract |
We isolated folistatin-related protein (FRP) as a novel autoantigen of rheumatoid arthritis. In order to clarify its pathological role, we tried to construct FRP-transgenic mouse, which is now under way, and tried to elucidate the in vitro and in vivo functions of FRP for synovial cells and their inflammation.
Transforming growth factor (TGF)-beta augmented FRP gene expression in synovial cells. FRP reduced synovial production of matrix metalloproteinase (MMP)1, MMP3 and prostaglandin E2, potent agonists of joint construction in RA. In contrast, autoantibodies to FRP from patients with RA increased their production by blocking FRP activity, probably in the autocrine system. Moreover, FRP down-regulated synovial expression of FOS (c-fos), which seemed responsible for the reduction in MMP1 and MMP3 caused by FRP.
We investigated the roles of FRP in a mouse model of arthritis, which was induced in BALB/c mice by injecting anti-type II collagen monoclonal antibody and lipopolysaccharide. Mice were treated with daily intraperitoneal injections of 20 μg of recombinant FRP. This treatment showed significant amelioration of the arthritis severity. Histologic analyses confirmed this finding and revealed the alleviation of cellular infiltration into the synovium as well as cartilage damage. Moreover, array analysis of the gene expression profile in FPR-treated arthritic lesions revealed a reduced expression of the c-fos, ets-2, IL6, MMP3, and MMP9 genes, some of which are thought to be associated with synovial inflammation and joint destruction.
These findings from in vitro and in vivo experiments suggest that FRP could be one of the key molecules in the treatment of inflammatory joint diseases such as RA.
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