CD44 IN RHEUMATOID SYNOVITIS

类风湿性滑膜炎中的 CD44

• 批准号: 6299866
• 负责人: KATALIN MIKECZ
• 金额: $ 22.63万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299866
• 关键词: CD44 molecule; SCID mouse; arthritis; articular cartilage; athymic mouse; cartilage transplantation; cell cell interaction; fibroblasts; human tissue; hyaluronate; interleukin 1; laboratory mouse; laboratory rat; leukocyte activation /transformation; molecular pathology; monoclonal antibody; proteoglycan; rheumatoid arthritis; synovitis; tumor necrosis factor alpha; xenotransplantation

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.

这项研究计划涉及透明质酸（HA）受体的作用 CD 44在类风湿性滑膜炎滑膜病理中的作用我们有 在蛋白多糖和胶原诱导的关节炎小鼠中证实 单克隆抗CD 44抗体消除了关节肿胀， 炎性白细胞浸润。我们的研究结果表明，CD 44 参与多种细胞-细胞和细胞-基质相互作用， 炎症的部位。CD 44和HA介导的炎症反应 滑膜炎目前尚不清楚。CD 44存在于滑膜细胞上， HA是滑液和细胞外基质的主要成分 在正常的关节。而CD 44和HA的含量则随着时间的延长而增加， 在炎症过程中非常明显。风湿性关节炎滑膜细胞 活化的白细胞表达CD 44变体同种型， 在正常滑膜中检测到。与正常关节相比，类风湿关节炎 滑膜组织产生HA分子， 基质和扩散到细胞外空间，从而影响关节 肿胀.白细胞，通过CD 44-HA相互作用，可以被募集， 由存在于滑膜间质室中的HA激活 组织.我们的初步结果表明，IL-1的产生和 TNF-α通过滑膜细胞被HA增强。此外，CD 44和 HA似乎与关节软骨的侵袭有关， 类风湿性血管翳 在这项研究中，我们将比较滑膜组织和细胞，从正常 和发炎的关节，在小鼠和人类系统中， HA和CD 44的分子和功能特性。我们将 描述了一些调节和信号传导机制， 有助于持续的白细胞和滑膜成纤维细胞活化。 我们还打算确定是否异常的细胞基质和细胞 类风湿性滑膜中的相互作用可以通过调节 CD 44功能。体外实验的结果将传达给 破坏性滑膜炎嵌合模型的体内研究， 移植到SCID小鼠中的人类风湿性滑膜和软骨。我们 我相信，这里提出的研究结果将提供一个 更好地理解关节炎中CD 44和HA介导的事件 过程，并为治疗干预开辟新的途径， 类风湿关节炎