Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis
Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis
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DOI：
10.1002/1529-0131(200002)43:2
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发表时间：
2000-02-01
影响因子：
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通讯作者：
Tanaka, S
中科院分区：
文献类型：
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作者：
Takayanagi, H;Iizuka, H;Tanaka, S
目标。通过探讨核因子KB配体受体激活因子(RANKL)/破骨细胞分化因子（ODF）的参与，阐明类风湿滑膜细胞培养过程中破骨细胞形成的机制。在巨噬细胞集落刺激因子和1,25-二羟基维生素D-3 （1,25[OH](2)D-3）存在下，利用分离膜过滤器评估类风湿滑膜成纤维细胞和外周血单核细胞（PBMC）共培养的破骨细胞形成。通过Northern blotting检测5例类风湿关节炎（RA）患者和巨细胞瘤（GCT）、骨肉瘤（OS）、骨关节炎（OA）患者滑膜组织中RANKL/ODF的表达。在与PBMC共培养的情况下，研究了RANKL/ODF的表达和滑膜成纤维细胞支持破骨细胞生成的能力，并通过酶联免疫吸附法测定了可溶性RANKL/ODF和骨保护素(OPG)/破骨细胞生成抑制因子（OCIF）。测定了OPG/OCIF对类风湿滑膜细胞原代培养和共培养体系中破骨细胞生成的影响。当与PBMC共培养时，滑膜成纤维细胞不诱导破骨细胞发生，Northern blotting显示RANKL/ODF在RA和GCT患者的所有组织中都高表达，而在OA或OS患者中则没有。培养的类风湿滑膜成纤维细胞在1,25(OH)(2)D-3存在下能有效诱导破骨细胞生成，同时RANKL/ODF表达上调，OPG/OCIF表达减少，OPG/OCIF可剂量依赖性地抑制滑膜细胞的破骨细胞生成。结论RANKL/ODF在滑膜成纤维细胞上表达，通过诱导破骨细胞生成参与类风湿骨破坏，是一个良好的治疗靶点。
Objective. To clarify the mechanism by which osteoclasts are formed in culture of rheumatoid synoviocytes by exploring the involvement of receptor activator of nuclear factor KB ligand (RANKL)/osteoclast differentiation factor (ODF).Methods. Osteoclast formation was evaluated in cocultures of rheumatoid synovial fibroblasts and peripheral blood mononuclear cells (PBMC) in the presence of macrophage colony stimulating factor and 1,25-dihydroxyvitamin D-3 (1,25[OH](2)D-3) utilizing separating membrane filters. RANKL/ODF expression was examined by Northern blotting in synovial tissues from 5 rheumatoid arthritis (RA) patients and tissues from patients with giant cell tumor (GCT), osteosarcoma (OS), and osteoarthritis (OA). RANKL/ODF expression and the ability of synovial fibroblasts to support osteoclastogenesis were investigated in coculture with PBMC in the presence or absence of 1,25(OH)(2)D-3, and soluble RANKL/ODF and osteoprotegerin (OPG)/ osteoclastogenesis inhibitory factor (OCIF) were measured by enzyme-linked immunosorbent assay. The effects of OPG/OCIF on the osteoclastogenesis in the primary culture of rheumatoid synoviocytes and the coculture system were determined.Results. Synovial fibroblasts did not induce osteoclastogenesis when separately cocultured with PBMC, Northern blotting revealed that RANKL/ODF was highly expressed in all tissues from RA and GCT patients, but not from OA or OS patients. Cultured rheumatoid synovial fibroblasts efficiently induced osteoclastogenesis in the presence of 1,25(OH)(2)D-3, which was accompanied by up-regulated expression of RANKL/ODF and decreased production of OPG/OCIF, Osteoclastogenesis from synoviocytes was dose-dependently inhibited by OPG/OCIF.Conclusion, RANKL/ODF expressed on synovial fibroblasts is involved in rheumatoid bone destruction by inducing osteoclastogenesis and would therefore be a good therapeutic target.