Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, Göteborg University, Box 480, 405 30 Göteborg, Sweden.
Arthritis Res Ther. 2011 Mar 7;13(2):R40. doi: 10.1186/ar3274.
Activated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction. The glycoprotein podoplanin is upregulated in the invasive front of several human cancers and has been associated with epithelial-mesenchymal transition, increased cell migration and tissue invasion. The aim of this study was to investigate whether podoplanin is expressed in areas of synovial transformation in RA and especially in promigratory RA-FLS.
Podoplanin expression in human synovial tissue from 18 RA patients and nine osteoarthritis (OA) patients was assessed by immunohistochemistry and confirmed by Western blot analysis. The expression was related to markers of synoviocytes and myofibroblasts detected by using confocal immunofluoresence microscopy. Expression of podoplanin, with or without the addition of proinflammatory cytokines and growth factors, in primary human FLS was evaluated by using flow cytometry.
Podoplanin was highly expressed in cadherin-11-positive cells throughout the synovial lining layer in RA. The expression was most pronounced in areas with lining layer hyperplasia and high matrix metalloproteinase 9 expression, where it coincided with upregulation of α-smooth muscle actin (α-sma). The synovium in OA was predominantly podoplanin-negative. Podoplanin was expressed in 50% of cultured primary FLSs, and the expression was increased by interleukin 1β, tumour necrosis factor α and transforming growth factor β receptor 1.
Here we show that podoplanin is highly expressed in FLSs of the invading synovial tissue in RA. The concomitant upregulation of α-sma and podoplanin in a subpopulation of FLSs indicates a myofibroblast phenotype. Proinflammatory mediators increased the podoplanin expression in cultured RA-FLS. We conclude that podoplanin might be involved in the synovial tissue transformation and increased migratory potential of activated FLSs in RA.
类风湿关节炎（RA）中活化的成纤维细胞样滑膜细胞（FLS）与肿瘤细胞具有许多共同特征，是滑膜组织转化和关节破坏的关键介质。糖蛋白 podoplanin 在几种人类癌症的侵袭前沿上调，并与上皮-间充质转化、细胞迁移和组织侵袭增加有关。本研究旨在探讨 podoplanin 是否在 RA 中滑膜转化区域表达，特别是在促迁移的 RA-FLS 中表达。
通过免疫组织化学评估 18 例 RA 患者和 9 例骨关节炎（OA）患者的人滑膜组织中 podoplanin 的表达，并通过 Western blot 分析进行验证。使用共聚焦免疫荧光显微镜检测 podoplanin 的表达与滑膜细胞和肌成纤维细胞的标志物相关。通过流式细胞术评估原发性人 FLS 中 podoplanin 的表达，同时添加促炎细胞因子和生长因子。
在 RA 的滑膜衬里层中，podoplanin 在整个 cadherin-11 阳性细胞中高度表达。在衬里层增生和高基质金属蛋白酶 9 表达的区域，表达最为明显，同时伴有α-平滑肌肌动蛋白（α-sma）的上调。OA 的滑膜主要为 podoplanin 阴性。50%的培养原代 FLS 表达 podoplanin，白细胞介素 1β、肿瘤坏死因子 α 和转化生长因子β受体 1 可增加其表达。
我们表明，在 RA 中侵袭性滑膜组织的 FLS 中 podoplanin 高度表达。α-sma 和 podoplanin 在 FLS 的一个亚群中同时上调表明其具有肌成纤维细胞表型。促炎介质增加了培养的 RA-FLS 中 podoplanin 的表达。我们得出结论，podoplanin 可能参与 RA 中活化的 FLS 滑膜组织转化和迁移能力的增加。
