脂联素促进B细胞表达RANKL介导类风湿关节炎骨侵蚀的机制研究

The overexpression of receptor activator of nuclear factor кB ligand (RANKL) functions as the molecular basis for the bone erosion of rheumatoid arthritis (RA). At present, studies have found that activated B cells are the main source of RANKL in RA joint tissues. Through secreting a large amount of RANKL, the activated B cells can induce osteoclast differentiation and further lead to the occurrence and development of bone erosion. Inflammatory factors like TNF-α and IL-17 serve as important media for the above process, which, however, fails to be completely blocked by corresponding targeted therapies, suggesting the presence of other factors that promote B cells to express RANKL. As a fat factor, adiponectin (AD) mediates the RA inflammation and tissue damage: being highly expressed in the joint of RA patients, we found that AD is positively correlated with synovial inflammation and bone erosion; AD can may aggravate the joint tissue injury and bone destruction in the CIA mouse model; AD receptor is highly expressed on the surface of B cells, and the exogenous AD can promote B cell activation and differentiation. Unfortunately, it remains unclear whether AD directly upregulates the molecular mechanism, by which B cells secrete RANKL to mediate RA bone erosion. Therefore, based on the existing studies, this project is designed to conduct a systematic exploration on the regulatory pathway of AD in mediating B cells to express RANKL through in vivo and in vitro experiments, thus providing a theoretical and experimental basis for clarifying AD-mediated RA bone erosion and further developing new clinical diagnosis and treatment means for RA.

核因子кB受体活化因子配体(RANKL)过表达是类风湿关节炎（RA）骨侵蚀的分子基础。目前发现，活化的B细胞是RA关节组织RANKL的主要来源。B细胞活化后分泌大量RANKL，诱导破骨细胞分化，导致骨侵蚀发生发展。TNF-α、IL-17等炎症因子是上述过程的重要介质，但相应靶向治疗尚不能阻断，提示还有其他因子促进B细胞表达RANKL。作为脂肪因子，脂联素（AD）介导了RA炎症与骨侵蚀：我们发现RA患者关节部位AD高表达并与滑膜炎症和骨侵蚀呈正相关；AD能加重RA模型鼠关节组织损伤与骨破坏；B细胞表面高表达AD受体、外源性AD可促进B细胞活化分化。但AD是否直接上调B细胞分泌RANKL介导RA骨侵蚀的分子机制尚不清楚。因此，本项目拟在已有研究基础上，通过体内体外实验，系统研究AD介导B细胞表达RANKL的调控通路，为阐明脂联素介导RA骨侵蚀、进一步发展RA新的临床诊疗手段提供理论和实验依据。

现代医学发展已经意识到脂肪细胞在炎症发生中有重要作用，我们近十年来的工作也证实作为脂肪因子，脂联素（Adiponectin，AD）介导了类风湿关节炎（RA）的炎症与组织破坏。类风湿关节炎炎性关节中脂肪细胞分泌的脂联素高表达后，滑膜炎症和骨侵蚀明显加重，表明脂联素的确与类风湿关节炎的局部炎症和组织损伤有关，但作用机制尚不清楚。本项目在已有研究基础上，通过体内体外实验研究发现RA患者关节部位AD高表达并与滑膜炎症和骨侵蚀呈正相关；AD能加重胶原诱导关节炎（CIA）小鼠关节组织损伤与骨破坏；B细胞表面高表达AD受体、外源性AD可促进B细胞活化分化并进而研究了AD诱导并促进了PI3K/Akt1和STAT3的激活B细胞的增殖和分化，而且STAT3与启动子结合在转录水平上调了Blimp-1基因的表达促进B细胞分化。总的来说，我们观察到AD通过通过PI3K/Akt1/STAT3轴促进B细胞增殖和分化且高表达RANKL的调控通路，为阐明脂联素介导RA骨侵蚀、进一步发展RA新的临床诊疗手段提供理论和实验依据，也为脂肪因子参与炎症提供新的依据，为进一步发展类风湿关节炎临床治疗提供新的靶点。