Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis.
Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis.
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DOI：
10.1172/jci17778
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发表时间：
2003-07
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影响因子：
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通讯作者：
N. Yamamoto;F. Sakai;S. Kon;J. Morimoto;Chiemi Kimura;H. Yamazaki;I. Okazaki;N. Seki;T. Fuj
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作者：
N. Yamamoto;F. Sakai;S. Kon;J. Morimoto;Chiemi Kimura;H. Yamazaki;I. Okazaki;N. Seki;T. Fuj
骨桥蛋白（OPN）在类风湿关节炎（RA）的发病机制中起着重要作用。然而，OPN作用的分子机制尚未阐明。从关节炎小鼠中获得的脾单核细胞表现出向凝血酶裂解的OPN而不是向全长OPN迁移的显著能力。迁移性单核细胞表达α 9和α 4整合素。由于凝血酶对骨桥蛋白的切割暴露了α 9和α 4整联蛋白识别的隐蔽表位，我们通过使用与SLAYGLR序列反应的特异性抗体（M5）研究了隐蔽表位SLAYGLR在鼠RA模型中的作用。M5抗体可以消除单核细胞向凝血酶裂解形式的OPN的迁移。重要的是，M5抗体可以抑制关节炎关节滑膜增生、骨侵蚀和炎性细胞浸润。因此，我们证明了一个隐藏的表位，鼠骨桥蛋白的SLAYGLR序列，是关键参与了RA的小鼠模型的发病机制。
It has been shown that osteopontin (OPN) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). However, the molecular mechanism of OPN action is yet to be elucidated. Splenic monocytes obtained from arthritic mice exhibited a significant capacity for cell migration toward thrombin-cleaved OPN but not toward full-length OPN. Migratory monocytes expressed alpha9 and alpha4 integrins. Since cleavage of OPN by thrombin exposes the cryptic epitope recognized by alpha9 and alpha4 integrins, we investigated the role of the cryptic epitope SLAYGLR in a murine RA model by using a specific antibody (M5) reacting to SLAYGLR sequence. The M5 antibody could abrogate monocyte migration toward the thrombin-cleaved form of OPN. Importantly, M5 antibody could inhibit the proliferation of synovium, bone erosion, and inflammatory cell infiltration in arthritic joints. Thus, we demonstrated that a cryptic epitope, the SLAYGLR sequence of murine OPN, is critically involved in the pathogenesis of a murine model of RA.