TNF-α抑制MSC成骨分化参与SLE骨质疏松信号通路机制研究

项目名称： TNF-α抑制MSC成骨分化参与SLE骨质疏松信号通路机制研究

项目编号： No.81202358

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学免疫学、法医学

项目作者： 汤郁

作者单位： 江苏大学

项目金额： 23万元

中文摘要： 目前认为系统性红斑狼疮(SLE)患者原发性骨质疏松是以TNF-α为主的炎症因子介导破骨细胞过度增殖、活化的结果，但尚缺乏狼疮患者炎症因子作用于成骨细胞的机制研究。我们前期初步研究发现SLE患者骨髓间充质干细胞(BMMSCs)成骨分化能力下降，BMP/Smad信号通路抑制以及NF-κB和MAPK/ERK通路过度活化。我们推测：SLE患者BMMSCs成骨分化障碍直接参与了骨质疏松的发病；其机制为TNF-α可能通过活化NF-κB或MAPK途径抑制BMMSCs的BMP /Smad信号通路从而参与骨疏松的病理过程。本项目将进一步研究SLE患者BMMSCs BMP-2 诱导下的成骨分化能力，在体内外观察TNF-α对BMMSC成骨分化的影响，阐明BMP/Smad、NF-κB和MAPK信号通路之间的调控机制,探索SLE骨质疏松新的发病机理，为临床治疗SLE骨质疏松提供新的靶点及理论依据。

中文关键词： 系统性红斑狼疮；间充质干细胞；成骨分化；肿瘤坏死因子；骨质疏松

英文摘要： The osteoporosis of patients with systemic lupus erythematosus (SLE) is thought to be the results of over-osteoclastogenesis induced by pro-inflammatory cytokines such as TNF-α. However, the molecular mechanisms involved in the osteoblastogenesis in SLE patients are not fully understood. We previously found that the capacity of osteoblastic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) from SLE patients was decreased, and the BMP/Smad signaling pathway was depressed. On the contrary, the NF-KB and MAPK/ERK pathways were over activated in the SLE BMMSCs. Thus here we suggest that activated NF-κB or MAPK pathway in SLE-BMMSCs inhibits the bone morphogeneic protein-2 (BMP-2) induced osteoblastic differentiation through BMP/Smad signaling pathway. In this study, we aim to investigate the BMP-2 induced osteoblastic capacity of BMMSCs from SLE patients and the TNF-αsignaling system in determining BMP-2-induced osteoblastic differentiation. Moreover, the regulatory mechanism between NFKB or MAPK and BMP/Smad signaling pathways will also be detected. We suggest the impaired osteoblastic differentiation may participate in the pathology of osteoporosis in SLE patients, and this theroay may be helpful for find any new medicine for the treatment for the osteoporosis in SLE patients.

英文关键词： Systemic lupus erythematosus；Mesenchymal stem cells；Osteoblastic differentiation；Tumor necrosis factor；Osteoporosis