CD44 IN RHEUMATOID SYNOVITIS

这项研究计划涉及透明质酸(HA)受体的作用 CD44在类风湿滑膜炎滑膜病理中的作用我们有 在蛋白多糖和胶原蛋白诱导的关节炎小鼠中得到证实 抗CD44的单抗可以消除关节肿胀和 炎性白细胞浸润。我们的结果表明CD44 参与多种细胞-细胞和细胞-基质的相互作用 发炎的部位。CD44和HA介导的炎症反应 滑膜炎目前尚不清楚。CD44存在于滑膜细胞上， 透明质酸是滑液和细胞外基质的主要成分 在正常的关节里。但CD44和HA的数量增加。 在炎症过程中戏剧性地。类风湿滑膜细胞 活化的白细胞表达CD44变异亚型，而不是 在正常滑膜中检测到。与正常关节相比，类风湿性关节炎 滑膜组织产生的HA分子与 基质并扩散到细胞外空间，从而影响关节 肿胀。白细胞，通过CD44-HA相互作用，可以被招募和 由存在于滑膜间质中的HA激活 组织。我们的初步结果表明，IL-1和IL-1的产生 HA可增强滑膜细胞分泌的肿瘤坏死因子-α。此外，CD44和 HA似乎与关节软骨的侵袭有关 类风湿性血管疙瘩。 在这项研究中，我们将比较正常滑膜组织和细胞 和发炎的关节，在小鼠和人类系统中，关于 HA和CD44的分子和功能特性。我们会 描述了一些监管和信号机制，这些机制可能 有助于持久的白细胞和滑膜成纤维细胞的激活。 我们还打算确定异常细胞-基质和细胞-细胞 类风湿滑膜中的相互作用可以通过调节 CD44功能。体外实验的结果将被传达到 一种破坏性滑膜炎嵌合模型的体内研究 人类风湿滑膜和软骨移植到SCID小鼠体内。我们 相信这里提出的研究结果将提供一个 更好地了解CD44和HA在关节炎中的介导作用 过程，并为治疗干预开辟了新的途径 类风湿关节炎。

This research proposal concerns the role of the hyaluronan (HA) receptor CD44 in synovial pathology during rheumatoid synovitis. We have demonstrated in mice with proteoglycan- and collagen-induced arthritis that a monoclonal anti-CD44 antibody eliminates joint swelling and inflammatory leukocyte infiltration. Our results suggest that CD44 participates in a variety of cell-cell and cell-matrix interactions at the site of inflammation. CD44- and HA-mediated events in inflammatory synovitis are current not understood. CD44 is present on synovial cells, and HA is a major constituent of synovial fluid and extracellular matrix in the normal joint. However, the amounts of CD44 and HA increase dramatically during inflammatory processes. Rheumatoid synovial cells and activated leukocytes express CD44 variant isoforms that are not detected in normal synovium. In contrast to normal joints, rheumatoid synovial tissue produces HA molecules that are poorly associated with matrix and diffuse into the extracellular space thus effecting joint swelling. Leukocytes, via the CD44-HA interaction, can be recruited and activated by HA present in the interstitial compartment of synovial tissue. Our preliminary results suggest that the production of IL-1 and TNF-alpha by synovial cells is augmented by HA. Furthermore, CD44 and HA appear to be associated with the invasion of articular cartilage by rheumatoid pannus. In this study, we will compare synovial tissues and cells from normal and inflamed joints, in both murine and human systems, with respect to the molecular and functional properties of HA and CD44. We will delineate some of the regulatory and signaling mechanisms which may contribute to persistent leukocyte and synovial fibroblast activation. We also intend to determine if abnormal cell-matrix and cell-cell interactions in the rheumatoid synovium can be corrected by modulating CD44 function. The results of in vitro experiments will be conveyed to in vivo studies on a chimeric model of destructive synovitis, utilizing human rheumatoid synovium and cartilage engrafted into SCID mice. We believe that the findings of the studies proposed here will provide a better understanding of CD44- and HA-mediated events in arthritic processes, and open new avenues for therapeutic intervention in rheumatoid arthritis.