Correlation of protease-activated receptor-2 expression and synovitis in rheumatoid and osteoarthritis
Correlation of protease-activated receptor-2 expression and synovitis in rheumatoid and osteoarthritis
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DOI：
10.1007/s00296-011-2102-9
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发表时间：
2012-10-01
影响因子：
4
通讯作者：
McInnes, Iain B.
中科院分区：
文献类型：
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作者：
Tindell, Alistair G.;Kelso, Elizabeth B.;McInnes, Iain B.
蛋白水解酶激活受体-2(PAR-2)是已知的促炎因子，越来越多的证据表明它是骨关节炎中的一种炎症成分。本研究探讨了滑膜炎症与PAR-2表达的关系，并对来自OA和RA患者的滑膜标本进行了组织学和免疫组织化学分析，同时对尸检获得的非关节炎标本进行了分析。样本还分析了PAR-4的表达，这种受体也可能具有促炎作用。分析包括比较炎症指标(滑膜厚度和单核细胞浸润)与PAR-2和PAR-4的表达。在PAR-2拮抗剂(ENMD-1068)或赋形剂存在的情况下，还分析了滑膜外植体产生肿瘤坏死因子α的情况。OA滑膜显示出炎症指标的异质性，一些样本与RA队列中的样本重叠，而另一些样本似乎与PM队列相似。PAR-2在滑膜衬里和间质中的表达分别与滑膜厚度(r=0.91)和单核细胞浸润(r=0.83)显著相关(P<；0.001)，在个体队列分析中仍有显著意义。在RA和OA滑膜中，PAR-2共定位于CD3和CD68细胞以及来自这些滑膜的成纤维细胞。PAR-4也有表达，但与炎症指标的关系要弱得多。OA滑膜中的炎症指标表现出相当大的变异性，但与PAR-2的表达密切相关，提示PAR-2在滑膜炎中表达上调。炎性指标的异质性与样本之间产生的肿瘤坏死因子α的巨大差异是平行的。这种细胞因子的分泌被ENMD-1068剂量依赖性地抑制，这为PAR-2在促进滑膜炎中的功能作用提供了证据。
Protease-activated receptor-2 (PAR-2) is known to be pro-inflammatory and increasing evidence points to an inflammatory component in osteoarthritis. This investigation examined the relationship between synovitis and PAR-2 expression, histological and immunohistochemical analysis being performed on synovial samples obtained from OA and RA patients, along with non-arthritic samples obtained by post mortem (PM). Samples were also analysed for PAR-4 expression, this receptor also having putative pro-inflammatory roles. Analysis involved comparison of inflammatory indices (synovial thickness and monocyte infiltration) with expression of PAR-2 and PAR-4. Synovial explants were also analysed for TNF alpha generation in the presence of a PAR-2 antagonist (ENMD-1068) or vehicle. OA synovia showed heterogeneity of inflammatory indicators, some samples overlapping with those from the RA cohort whilst others appeared similar to the PM cohort. PAR-2 expression, both in the lining layer and the interstitium, correlated strongly and significantly with synovial thickness (r = 0.91) and monocyte infiltration (r = 0.83), respectively (P < 0.001 in both cases), and this remains significant on individual cohort analysis. PAR-2 was co-localised to CD3 and CD68 cells in RA and OA synovium as well as fibroblasts derived from these synovia. PAR-4 was also expressed, but the relationship with inflammatory indicators was substantially weaker. Inflammatory indicators in OA synovia showed considerable variability, but correlated strongly with PAR-2 expression, suggesting PAR-2 upregulation in synovitis. Heterogeneity of inflammatory indicators was paralleled by wide variation in TNF alpha generation between samples. Secretion of this cytokine was dose-dependently inhibited by ENMD-1068, providing evidence of a functional role for PAR-2 in promoting synovitis.