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

核因子-kB受体激活剂配体(RANKL)是骨免疫学中的关键分子。本研究的目的是分析RANKL刺激的分泌细胞(DC)的细胞转移在MRL/LPR小鼠自身免疫性关节病发生发展中的作用，并探讨自身免疫反应与RANKL介导的破骨细胞生成的可能关系。用RANKL和鸡II型胶原(CII)刺激MRL/LPR小鼠成熟的骨髓DC(BMDC)，并将其皮下移植1~3次。与未转移和非冲击DC转移的MRL/LPR小鼠相比，RANKL/CII DC转移的小鼠加速了自身免疫性关节炎的骨破坏。在RANKL/CII DC转移的小鼠中，检测到T细胞的记忆表型显著转变。结果表明，RANKL/CII小鼠DC的TRAF6、c-FMS、c-Fos、PU.1、c-Src等MHC-II类和RANKL相关分子的表达明显上调。此外，RANKL/CII DC转移小鼠的骨髓培养结果显示，与未转移DC小鼠相比，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，通过上调外周T细胞活化诱导的细胞死亡(AICD)，保护了自身免疫性关节炎的发生，减轻了脾肿大和淋巴病变。这些结果表明，RANKL通路在类风湿关节炎小鼠模型中对自身免疫性关节病的免疫调节起着至关重要的作用。

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.