Protection of joint destruction through suppression of integrin signaling synovial cells in rheumatoid
| Project/Area Number |
14571375
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
YASUDA Tadashi Kyoto University, Faculty of Medicine, assistant Professor, 医学研究科, 助手 (40314223)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Takashi Kyoto University, Faculty of Medicine, Professor, 医学研究科, 教授 (10201675)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | synovial cells / integrin / rheumatoid arthritis / MMP / fibronectin fragment / MAP kinase / joint destruction / pannus / フィブロネクチンフラグメント |
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| Research Abstract |
The process of cartilage invasion by pannus is poorly understood, although collagenase activity has been shown to be required for the process. Besides α5 and β1 integrin subunits, rheumatoid synovial fibroblasts (RSF) neoexpress α4 integrin subunit at the pannus-cartilage junction. The purpose of this study was to investigate the role of α4β1 integrin signaling in matrix metalloproteinase (MMP) production by RSF. RSF were obtained from knee joints at replacement surgery for patients with rheumatoid arthritis, and cultured in monolayer. Immunoprecipitation revealed the presence of α4 integrin subunit in cultured RSF. Treatment with COOH-terminal heparin-binding fibronectin fragment (HBFN-f) and the synthetic peptide CS-1 derived from HBFN-f both of which can bind α4β1 integrin, resulted in enhanced secretion of MMP-1, MMP-3, and MMP-13 from RSF in a dose-dependent manner, while RSF incubated with control peptide or without peptides secreted barely detectable levels of those MMPs. Anti-α4 integrin antibody blocked the action of HBFN-f. Inhibition studies with specific MAP kinase inhibitors revealed that MMP production through α4β1 integrin involved ERK, p38, and JNK.
Ligation of α4β1 integrin with the ligand caused significant production of collagenases (MMP-1 and MMP-13) and stromelysin 1 (MMP-3) by RSF. Thus, stimulation of α4β1 integrin on RSF at the pannus-cartilage junction may contribute to cartilage destruction by pannus through MMP induction. MAP kinase inhibition may be effective for suppression of α4β1 integrin signaling.
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Report
(3 results)
Research Products
(7 results)
