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

核因子-κ B受体激活因子配体（RANKL）是骨免疫学的关键分子。本研究旨在分析RANKL刺激的树突状细胞（DCs）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（CII）刺激来自MRL/lpr小鼠的成熟骨髓DC（BMDC），并将其皮下转移至MRL/lpr小鼠中一次或三次。与大量非转移和非脉冲DC转移、CII DC转移MRL/lpr小鼠相比，在RANKL/CII DC转移小鼠中观察到自身免疫性关节炎伴骨破坏加速。在RANKL/CII DC转移小鼠中检测到T细胞记忆表型的显著变化。结果表明，RANKL/CII DC转染小鼠DC的MHC II类分子和RANKL相关分子TRAF 6、c-Fms、c-Fos、PU.1、c-Src的表达显著上调。此外，RANKL/CII DC转移小鼠的骨髓培养物导致破骨细胞形成和骨吸收增加，与非DC转移小鼠相比。另一方面，将RANKL/CII DC三次转移到MRL/lpr小鼠中保护自身免疫性关节炎的发展，并通过上调外周T细胞的活化诱导细胞死亡（AICD）来减少脾肿大和淋巴结病。这些结果表明，RANKL途径在类风湿性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.