Mechanism of bone destruction due to Rheumatoid Arthritis in the fields of Osteoimmunology

骨免疫学领域类风湿关节炎引起的骨破坏机制

基本信息

批准号：
15390637
负责人：
MORIYAMA Keiji
金额：
$ 9.22万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390637/
关键词：
Rheumatoid arthritis Estrogen RANKL Bone destruction MRL lpr mice Dendritic cell Osteoclast MRI II型コラーゲン

项目摘要

Receptor activator of NF-kB ligand (RANKL) is known to be a key molecule of the osteoimmunology. The aim of this study was to analyze the effect of cell transfer of dedritic cells (DCs) stimulated with RANKL on the development of autoimmune arthropathy in MRL/lpr mice, and to evaluate the possible relationship between autoimmune responses and RANKL-mediated osteoclastogenesis. Matured bone marrow DC (BMDC) from MRL/lpr mice were stimulated with RANKL and chick type II collagen (CII), and were subcutaneously transferred one or three times into MRL/lpr mice. Acceleration of autoimmune arthritis with bone destruction was observed in RANKL/CII DC-transferred mice compared with the legions of non-transferred and non-pulsed DC-transferred, CII DC-transferred MRL/lpr mice. A significant shift to memory phenotypes of T cells was detected in RANKL/CII DC-transferred mice. It was shown that the expressions of MHC class II and RANKL-associated molecules including TRAF6, c-Fms, c-Fos, PU.1 c-Src, of the DCs from RANKL/CII DC-transferred mice were significantly upregulated. In addition, the bone marrow culture from RANKL/CII DC-transferred mice resulted in the increases of osteoclast formation and bone resorption, compared with those of non-DC-transferred mice. On the other hand, three times of transfer of RANKL/CII DC into MRL/lpr mice protected the development of autoimmune arthritis, and reduced the splenomegaly and lymphadenopathy through upregulation of Activation-induced cell death (AICD) of peripheral T cells. These results indicate that RANKL pathway plays a crucial role for immunomodulation of autoimmune arthropathy in a murine model for rheumatoid arthritis.

NF-kB 配体受体激活剂 (RANKL) 被认为是骨免疫学的关键分子。本研究的目的是分析 RANKL 刺激的树突状细胞 (DC) 的细胞转移对 MRL/lpr 小鼠自身免疫性关节病发展的影响，并评估自身免疫反应与 RANKL 介导的破骨细胞生成之间的可能关系。用RANKL和鸡II型胶原蛋白（CII）刺激来自MRL/lpr小鼠的成熟骨髓DC（BMDC），并皮下转移至MRL/lpr小鼠体内一到三次。与大量未转移和非脉冲DC转移的、CII DC转移的MRL/lpr小鼠相比，在RANKL/CII DC转移的小鼠中观察到自身免疫性关节炎和骨破坏的加速。在 RANKL/CII DC 移植小鼠中检测到 T 细胞记忆表型的显着转变。结果显示，RANKL/CII DC 移植小鼠的 DC 中 MHC II 类和 RANKL 相关分子（包括 TRAF6、c-Fms、c-Fos、PU.1 c-Src）的表达显着上调。此外，与非DC移植小鼠相比，RANKL/CII DC移植小鼠的骨髓培养导致破骨细胞形成和骨吸收增加。另一方面，将 RANKL/CII DC 三次转移到 MRL/lpr 小鼠体内可保护自身免疫性关节炎的发展，并通过上调外周 T 细胞的激活诱导细胞死亡 (AICD) 来减少脾肿大和淋巴结肿大。这些结果表明，RANKL 通路在类风湿性关节炎小鼠模型中的自身免疫性关节病的免疫调节中发挥着至关重要的作用。