Busso Nathalie, Morard Carole, Salvi Roberto, Péclat Veronique, So Alexander
Laboratoire de Rhumatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Arthritis Rheum. 2003 Mar;48(3):651-9. doi: 10.1002/art.10869.
Clinical and experimental evidence suggests that extravascular fibrin deposition in arthritic joints is prominent and deleterious. The aim of this study was to investigate the contributions of tissue factor (TF) and its inhibitor, TF pathway inhibitor (TFPI), in arthritis.
Synovial tissue specimens obtained from 10 patients with rheumatoid arthritis (RA) and 12 patients with osteoarthritis (OA) were scored histologically for inflammation and fibrin content. TF and TFPI levels were assayed at antigenic and functional levels. TF messenger RNA (mRNA) levels were determined using RNase protection assays. The effect of TF inhibition in murine antigen-induced arthritis (AIA) was assessed by administering systemically active site-blocked activated factor VIIa (FVIIai).
Functional TF activity was significantly increased in synovial membranes from RA patients compared with those from OA patients. In contrast, no difference in TF mRNA and TF antigenic levels was observed between these 2 groups. This discrepancy can be accounted for by TFPI, because we observed a negative correlation between TF activity and TFPI activity. There was a significant difference between the RA and OA groups in terms of synovial inflammation, with more inflammation observed in the RA group. Most importantly, TF activity was associated with fibrin (P = 0.024) and with histologic inflammation (P = 0.03) scores. In AIA, inhibition of TF-induced coagulation by FVIIai led, on day 9 of arthritis, to decreased synovial thickness and decreased articular cartilage damage, although only the latter difference between controls and treated mice reached significance (P < 0.04). Finally, in FVIIai-treated mice, there was a strong negative association between the prothrombin time and intraarticular fibrin deposition.
Our results show that TF expression in arthritic synovial tissue favors extravascular coagulation and may play a role in inflammation in RA. In this context, TF inhibitors may be of therapeutic value.
临床和实验证据表明，关节炎关节中的血管外纤维蛋白沉积显著且有害。本研究旨在探讨组织因子（TF）及其抑制剂TF途径抑制剂（TFPI）在关节炎中的作用。
对从10例类风湿关节炎（RA）患者和12例骨关节炎（OA）患者获取的滑膜组织标本进行组织学炎症和纤维蛋白含量评分。在抗原和功能水平上检测TF和TFPI水平。使用核糖核酸酶保护试验测定TF信使核糖核酸（mRNA）水平。通过全身给予活性位点阻断的活化因子VIIa（FVIIai）评估TF抑制在小鼠抗原诱导性关节炎（AIA）中的作用。
与OA患者的滑膜相比，RA患者滑膜中的功能性TF活性显著增加。相比之下，这两组之间未观察到TF mRNA和TF抗原水平的差异。这种差异可以用TFPI来解释，因为我们观察到TF活性与TFPI活性之间呈负相关。RA组和OA组在滑膜炎症方面存在显著差异，RA组炎症更明显。最重要的是，TF活性与纤维蛋白（P = 0.024）和组织学炎症（P = 0.03）评分相关。在AIA中，FVIIai对TF诱导的凝血的抑制作用在关节炎第9天时导致滑膜厚度降低和关节软骨损伤减轻，尽管对照组和治疗组小鼠之间只有后者的差异具有统计学意义（P < 0.04）。最后，在FVIIai治疗的小鼠中，凝血酶原时间与关节内纤维蛋白沉积之间存在强烈的负相关。
我们的结果表明，关节炎滑膜组织中的TF表达有利于血管外凝血，可能在RA炎症中起作用。在此背景下，TF抑制剂可能具有治疗价值。
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