核因子κB受体激活剂配体/破骨细胞分化因子在类风湿关节炎滑膜细胞破骨细胞生成中的作用。

Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis.

作者信息

Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, Koshihara Y, Oda H, Nakamura K, Tanaka S

机构信息

The University of Tokyo, Japan.

出版信息

Arthritis Rheum. 2000 Feb;43(2):259-69. doi: 10.1002/1529-0131(200002)43:2<259::AID-ANR4>3.0.CO;2-W.

DOI:10.1002/1529-0131(200002)43:2<259::AID-ANR4>3.0.CO;2-W

PMID:10693864

Abstract

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 kappaB 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 D3 (1,25[OH]2D3) 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)2D3, 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)2D3, 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.

摘要

目的

通过探究核因子κB受体活化因子配体（RANKL）/破骨细胞分化因子（ODF）的参与情况，阐明类风湿性滑膜细胞培养中破骨细胞形成的机制。

方法

利用分离膜滤器，在巨噬细胞集落刺激因子和1,25-二羟基维生素D3（1,25[OH]2D3）存在的情况下，评估类风湿性滑膜成纤维细胞与外周血单个核细胞（PBMC）共培养时的破骨细胞形成情况。通过Northern印迹法检测5例类风湿性关节炎（RA）患者滑膜组织以及巨细胞瘤（GCT）、骨肉瘤（OS）和骨关节炎（OA）患者组织中RANKL/ODF的表达。在有或无1,25(OH)2D3的情况下，研究滑膜成纤维细胞与PBMC共培养时RANKL/ODF的表达以及支持破骨细胞生成的能力，并通过酶联免疫吸附测定法检测可溶性RANKL/ODF和骨保护素（OPG）/破骨细胞生成抑制因子（OCIF）。确定OPG/OCIF对类风湿性滑膜细胞原代培养和共培养系统中破骨细胞生成的影响。

结果

滑膜成纤维细胞与PBMC单独共培养时不诱导破骨细胞生成。Northern印迹显示，RANKL/ODF在RA和GCT患者的所有组织中高表达，而在OA或OS患者的组织中不表达。培养的类风湿性滑膜成纤维细胞在1,25(OH)2D3存在的情况下有效诱导破骨细胞生成，同时伴有RANKL/ODF表达上调和OPG/OCIF产生减少。OPG/OCIF剂量依赖性地抑制滑膜细胞的破骨细胞生成。