| Project/Area Number |
12670443
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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 |
内科学一般
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| Research Institution | St. Marianna University School of Medicine |
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Principal Investigator |
SUZUKI Yasuo St.Marianna Univ., Sch of Med, Associate Professor, 医学部, 助教授 (90129495)
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| Co-Investigator(Kenkyū-buntansha) |
TSUTSUMI Yutaka Fujita Health Univ. Sch of Med, Professor, 医学部, 教授 (80138643)
UEHARA Ritsuko St.Marianna Univ., Sch of Med, Lecturer, 医学部, 助手 (10318933)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | RHEUMATOID ARTHRITIS / BONE DESTRUCTION / IN VITRO MODEL / OSTEOCLAST / RANKL / RANK / TNFα / SYNOVIOCYTE |
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| Research Abstract |
Osteoclasts may be involved in the process of rheumatoid bone destruction. To test this hypothesis, we developed an in vitro model of bone destruction by osteoclast-like cells derived from cultured rheumatoid synovial tissue without using any inducers. Synovial tissues were obtained from rheumatoid arthritis and osteoarthritis patients and tissue pieces of about 2 mm^3 that contained synovial lining were cultured. Multinucleated cells derived from cultured synovial tissues were studied cytochemically and morphologically for osteoclast-specific markers. Fibroblast-like and macrophage-like cells from the tissue pieces proliferated in the coexistence of lymphocytes. After 14 days of culture, multinucleated cells with tartrate-resistant acid phosphatase activity appeared. These cells expressed vacuolar H^+ -ATPase, the vitronectin receptor, and cathepsin K. Although [^<125>l]-salmon calcitonin binding was very low, the cells contained ringed structures of F-actin and showed strong bone res
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orbing activity on ivory slices. Proliferation of macrophage-like cells and formation of multinucleated cells continued during 6 months of culture in the presence of fibroblast-like cells. The bone-resorbing activity of multinucleated cells derived from rheumatoid synovial tissue was much higher than that of cells from osteoarthritis synovial tissue, and was related to the disease activity of rheumatoid arthritis Our culture system reproduced in vitro the process of bone destruction by rheumatoid synovium, including the proliferation and fusion of precursor cells, polarization, activation, and bone tissue resorption. To clarify the molecular mechanism of the differentiation from synovial cells to osteoclasts, we tested the involvement of RNAKL/RANK-dependent or independent pathway. Blocking of RANKL/RANK-dependent signals by osteoprotergrin, a decoy receptor of RANKL significantly reduced bone resorption by cultured rheumatoid synovium. Blockade of TNFα action mediated through TNF-recptor II also decreased in vitrop bone resorption. Our data suggest that both RANKL-dependent and independent signals might be involved in the formation of osteoclasts in the in vitro model of bone derstruction. Less
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