脂联素介导类风湿关节炎骨侵蚀机制的研究

The adipocytes in joint have long been considered as none-bioactive cells mainly devoted to energy storage. During the past 6 years, we have shown that adiponectin (AD), one of adipokines produced by adipocytes, is highly expressed in the inflammated joint of rheumatoid arthritis （RA） patients and correlats closely with progressive bone erosion, but the mechanism remained largely unclear. The most important pathologic changes at chronic inflammatory stage of RA include synovitisis, synovial hyperplasia and angiogenesis，which involves fibroblast-like synoviocyte (FLs) and endothelial cells. Base on our previous studies and current findings, we hypothesize that AD may mediate synovial inflammation and bone erosion of RA through the interaction with stromal microenvironment and RANKL-osteoclast pathway. In this study, we will test our hypothesis with four specific aims. Aim 1) Characterize the function of AD in modulating joint stromal microenvironment. Aim 2) Examine whether AD promotes the differntiation and activation of Th1 and Th17 cells ; Aim 3) Elucidate the molecular mechanism by which AD modulates stromal microenvironment via activating "RANKL-osteoclast" pathway; Aim 4) Determine whether local AD gene silencing could ameliorate arthritis development in CIA mice. Taken together, our proposed studies will determine a critical role of AD during the pathogenesis of autoimmune arthritis, which may contribute to the identification of AD as a new therapeutic target for RA treatment.

传统认为关节脂肪细胞仅是无活性能量储存细胞，我们六年来的工作基础证实类风湿关节炎（RA）炎性关节中脂肪细胞分泌的脂联素(Adiponection，AD)高表达后，骨侵蚀明显加重，其作用机制尚不清楚。滑膜炎症/增生和血管翳是RA慢性炎症中最突出的病理特征，此过程涉及两个最基本的基质细胞-滑膜成纤维细胞和内皮细胞。我们提出假说：AD通过影响关节滑膜基质细胞微环境和"RNAKL-破骨细胞"通路参与RA骨侵蚀过程。本研究将通过构建重组腺病毒载体、RNA干扰、流式细胞仪、免疫组织化学、Real-time PCR等技术，围绕AD对滑膜基质内环境中滑膜细胞生物学特性、细胞因子分泌、血管翳形成、Th17细胞分化，及对RANKL表达和破骨细胞功能的影响，阐明AD介导RA骨侵蚀过程的机制；并明确关节局部抑制AD表达是否可以在胶原诱导关节炎鼠模型发病过程中抑制滑膜炎症和骨侵蚀，为RA寻找新的治疗靶标奠定基础。

该课题组多年的研究基础及文献报道明确提示：脂肪因子脂联素在RA中绝不是“无关旁观者”，它们参与RA “骨侵蚀”病理过程。在前期工作基础上，本课题回答将两个问题：脂联素在RA关节局部为何表现出与全身完全不同的“致炎”属性，是如何介导了RA “骨侵蚀”病理过程？抑制脂联素表达能否成为阻止RA炎症和骨侵蚀的新靶标？. 该课题主要围绕炎性关节环境中的两个重要细胞T细胞及滑膜成纤维细胞，揭示了脂联素介导RA骨侵蚀过程的分子机制。该课题首次从体内及体外实验两方面报道了脂联素不仅能促进Th17细胞分化，还能促进RA滑膜成纤维细胞增殖、迁移及侵袭并抑制其凋亡，促进其分泌RANKL及多种炎症因子，通过影响T细胞分化及RA滑膜成纤维细胞的生物学活性参与骨侵蚀。. 深入揭示脂联素在RA局部的作用机制和靶点，对于深入理解RA慢性炎症和骨侵蚀的机理和全面揭示脂联素的功能有重要意义，可能为RA诊疗带来新思路和新方法。该课题体内实验和体外细胞实验紧密结合，观察脂联素对炎症及骨侵蚀的影响，研究思路缜密，采用过表达和沉默两方面相互印证，研究结果真实可靠，有说服力。