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表达。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。这些结果表明CD44 和HA在滑膜细胞和滑膜细胞间的黏附作用中起重要作用 关节炎症过程中的白细胞。还利用了CD44和HA 在类风湿血管疙瘩侵犯关节软骨的过程中。CD44- 然而，炎症滑膜炎中HA介导的事件却很少 明白了。CD44存在于滑膜细胞上，HA是其组成成分 然而，在正常关节中，它们的量 在炎症过程中增加。类风湿滑膜细胞和 激活的白细胞表达未被检测到的CD44变异亚型 在正常滑膜中。与正常关节相比，类风湿滑膜 组织会产生大量的透明质酸，这与 并扩散到关节周围组织，造成关节肿胀。 通过CD44-HA的相互作用，白细胞可以被招募和激活 透明质酸存在于滑膜组织的间质中。我们的 初步结果表明，除HA外，白细胞CD44是 能够识别滑膜表达的另一种配体 关节炎关节的细胞。 在这项研究中，我们将比较正常和类风湿滑膜细胞，在 小鼠和人类系统，关于HA结合和基质 新陈代谢，并确定滑膜细胞-基质异常相互作用 由类风湿滑膜细胞显示，可通过调制纠正 CD44功能。我们将鉴定可能起作用的滑膜蛋白 作为白细胞CD44的配体，有可能作为一种 消炎治疗的靶点。体外实验结果 实验将被传达到对小鼠模型的体内研究 炎症性关节炎，也是对嵌合模型的破坏性 滑膜炎，利用人类类风湿滑膜和软骨移植 转化成SCID小鼠。我们相信研究结果建议 在这里将提供一个更好的理解的病理作用 CD44和HA驱动的关节炎过程中的事件，并开辟了新的途径 用于类风湿关节炎的治疗干预。

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. These results suggest that CD44 and HA are important for adhesive interactions among synovial cells and leukocytes during joint inflammation. CD44 and HA are also utilized during the invasion of articular cartilage by rheumatoid pannus. CD44- and HA-mediated events in inflammatory synovitis, however, are poorly understood. CD44 is present on synovial cells and HA is a constituent of extracellular matrix in the normal joint, however, their amounts increase 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 large amounts of HA which are poorly associated with matrix and diffuse into periarticular tissues, 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, in addition to HA, leukocyte CD44 is capable of recognizing another ligand which is expressed by synovial cells of arthritic joints. In this study we will compare normal and rheumatoid synovial cells, in both murine and human systems, with respect to HA binding and matrix metabolism, and determine if abnormal synoviocyte-matrix interactions displayed by rheumatoid synovial cells, can be corrected by modulating CD44 function. We will identify the synovial protein which may serve as a ligand for leukocyte CD44, and could be potentially used as a target for anti-inflammatory therapy. The results of in vitro experiments will be conveyed to in vivo studies on a murine model of inflammatory arthritis, and also 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 the pathological roles of CD44- and HA-driven events in arthritic processes, and open new avenues for therapeutic intervention in rheumatoid arthritis.