Expression patterns of CD44 and CD44 splice variants in patients with rheumatoid arthritis.
Expression patterns of CD44 and CD44 splice variants in patients with rheumatoid arthritis.
复制标题
DOI：
--
复制
发表时间：
2012
影响因子：
3.7
通讯作者：
J. Grisar;M. Munk;C. Steiner;L. Amoyo-Minar;M. Tohidast-Akrad;P. Zenz;G. Steiner;J. Smolen
中科院分区：
文献类型：
--
作者：
J. Grisar;M. Munk;C. Steiner;L. Amoyo-Minar;M. Tohidast-Akrad;P. Zenz;G. Steiner;J. Smolen
目的CD44参与类风湿关节炎(RA)的发病机制。通过选择性剪接，可以产生多种CD44亚型，这些亚型可能在炎症过程中发挥不同的作用。因此，我们研究了各种CD44剪接变异体在RA患者循环和滑膜组织中的表达及其与临床特征的相关性。方法采用流式细胞术检测46例RA患者和36例健康人外周血单核细胞中CD44剪接变异体的表达。用免疫组织化学方法检测CD44剪接变异体在RA和OA患者滑膜组织中的表达，并观察封闭CD44v4对类风湿关节炎成纤维样滑膜细胞(FLS)的影响。结果CD44和CD44v3在单核细胞上的表达在糜烂性疾病组明显低于无放射性进展组(P<0.05)，CD44v3在单核细胞上的表达显著低于无进展组(P<0.01)。单核细胞表面CD44v6表达与临床疾病活动指数(r=0.34，p<；0.05)和C反应蛋白水平(r=0.37，p<；0.02)显著相关。免疫组织化学分析显示，大多数变异体在RA滑膜中的表达明显高于在OA滑膜中的表达。尤其是CD44v4、CD44v6和CD44v7-8在RA衬里和血管内皮细胞中均有较高的表达。阻断CD44v4可使RA-FLS的增殖减少至对照组的68±8%(p<；0.02)，并降低IL-1？m RNA的表达(p<；0.05)。结论类风湿关节炎患者滑膜组织中CD44剪接变异体的表达普遍高于骨性关节炎患者。CD44v3在单核细胞上的表达与RA-FLS侵蚀性疾病的发生及CD44v4的阻断对功能的影响呈负相关，提示该剪接变异体在RA-FLS中的致病作用有待进一步研究。
OBJECTIVES It has been suggested that CD44 is involved in the pathogenesis of rheumatoid arthritis (RA). By alternative splicing, numerous CD44 isoforms can be generated which may play different roles the inflammatory process. We therefore studied the expression of various CD44 splicevariants in the circulation and synovial tissue of patients with RA and correlated expression with clinical features. METHODS Expression of distinct CD44 splice variants was analysed by FACS in peripheral monocytes of 46 RA patients and 36 healthy controls. Expression of CD44 splice variants in synovial tissue of RA and OA patients was analysed by immunohistochemistry and the effects of blocking CD44v4 on RA-fibroblast like synoviocytes (FLS) were studied. RESULTS On monocytes, the expression of CD44 and CD44v3 was significantly lower in patients with erosive disease than in those without radiographic progression (p<0.05 for CD44 and p<0.01 for CD44v3). CD44v6 on monocytes was significantly associated with the clinical disease activity index (r=0.34, p<0.05) and CRP-levels (r=0.37, p<0.02). Immunhistochemical analyses revealed that most variants were expressed to a significantly higher extent in RA than in OA synovial membranes. Particularly the variants CD44v4, CD44v6 and CD44v7-8 were highly expressed in the RA lining and also abundantly in the endothelium. Blocking CD44v4 in RA-FLS reduced the proliferation to 68±8% (p<0.02) when compared to control experiments and led to a reduction in IL-1ß mRNA expression (p<0.05). CONCLUSIONS Expression of CD44 splice variants is generally increased in the synovial lining of RA patients when compared to OA. The inverse association of CD44v3 expression on monocytes with the development of erosive disease and the functional impacts of CD44v4 blockade in RA-FLS suggests a pathogenetic role of this splice variants which needs to be further investigated.