Thrombin-activatable carboxypeptidase B cleavage of osteopontin regulates neutrophil survival and synoviocyte binding in rheumatoid arthritis.
Thrombin-activatable carboxypeptidase B cleavage of osteopontin regulates neutrophil survival and synoviocyte binding in rheumatoid arthritis.
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DOI：
10.1002/art.24814
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发表时间：
2009-10
影响因子：
--
通讯作者：
Leung, Lawrence L. K.
中科院分区：
文献类型：
--
作者：
Sharif, Shadi A.;Du, Xiaoyan;Myles, Timothy;Song, Jason J.;Price, Elizabeth;Lee, David M.;Goodman, Stuart B.;Nagashima, Mariko;Morser, John;Robinson, William H.;Leung, Lawrence L. K.
骨桥蛋白(OPN)是类风湿关节炎(RA)中重要的促炎细胞因子。OPN可以被凝血酶切割，导致OPN-Arg(OPN-R)，并暴露出隐匿的C端α4β1和α9β1整合素结合基序(SVVYGLR)。凝血酶激活的羧肽酶B又称凝血酶激活的纤溶抑制物(TAFI)，它能去除骨桥蛋白受体的C端精氨酸，生成骨桥蛋白亮氨酸(OPN-Leu)，并阻断其增强的细胞结合。我们研究了OPN-R和OPN-L在以下两个方面的作用：(1)滑膜细胞黏附，促进侵袭性血管内膜的形成；(2)中性粒细胞存活，影响炎性渗出。我们建立了针对OPN-R和OPN-L的ELISA，并证实了OPN-R和OPN-L在RA中的升高，但在骨性关节炎或银屑病关节炎和滑液样本中不存在。OPN-R、OPN-L水平与肿瘤坏死因子、α、IL-6等多种炎性细胞因子相关。免疫组织化学分析显示OPN-FL在RA滑膜中有较强的表达，但OPN-R在RA滑膜中有少量表达，提示被切割的OPN被释放到滑液中。在细胞检测中，OPN-FL、OPN-R和OPN-L对中性粒细胞具有抗凋亡作用。OPN-R而不是OPN-L通过SVVYGLR与α4β1结合来增强RA成纤维细胞样滑膜细胞的结合。OPN-R的凝血酶激活和凝血酶可激活的体外循环灭活(OPN-L)发生在RA炎症关节的局部。我们的数据表明，凝血酶激活的体外循环通过调节中性粒细胞的活性和减少滑膜细胞的黏附，在类风湿关节炎中发挥着中心的稳态作用。
Osteopontin (OPN) is a pro-inflammatory cytokine important in rheumatoid arthritis (RA). OPN can be cleaved by thrombin, leading to OPN-Arg (OPN-R) and exposing the cryptic C-terminal α4β1 and α9β1 integrin-binding motif (SVVYGLR). Thrombin-activatable carboxypeptidase B (CPB), also termed thrombin-activatable fibrinolysis inhibitor (TAFI), removes the C-terminal arginine from OPN-R, generating OPN-Leu (OPN-L) and abrogating its enhanced cell binding. We investigated the roles of OPN-R and OPN-L in: (i) synoviocyte adhesion, which contributes to formation of invasive pannus, and (ii) neutrophil survival, which affects inflammatory infiltrates, in RA. We developed ELISAs specific for OPN-R and OPN-L, and demonstrate elevations of OPN-R and OPN-L in RA, but not in osteoarthritis or psoriatic arthritis, synovial fluid samples. OPN-R and OPN-L levels correlated with multiple inflammatory cytokines including TNFα and IL-6. Immunohistochemical analyses demonstrated robust expression of OPN-FL, but minimal OPN-R, in RA synovium, suggesting that cleaved OPN is released into the synovial fluid. In cellular assays, OPN-FL, and to a lesser extent OPN-R and OPN-L, had an anti-apoptotic effect on neutrophils. OPN-R, but not OPN-L, augmented RA fibroblast-like synoviocyte binding mediated by SVVYGLR binding to α4β1. Thrombin activation of OPN (OPN-R) and its subsequent inactivation by thrombin-activatable CPB (OPN-L) occurs locally within inflamed joints in RA. Our data suggest that thrombin-activatable CPB plays a central homeostatic role in RA, by regulating neutrophil viability and reducing synoviocyte adhesion.
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