Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis
Midkine, a heparin-binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis
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DOI：
10.1002/art.20175
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发表时间：
2004-05-01
影响因子：
--
通讯作者：
Muramatsu, T
中科院分区：
文献类型：
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作者：
Maruyama, K;Muramatsu, H;Muramatsu, T
Objective.中期因子（MK）是一种肝素结合生长因子，可促进各种细胞的生长、存活和迁移。MK在炎性细胞迁移中的重要作用已在MK基因缺陷小鼠（Mdk（-/-）小鼠）中得到证实。本研究旨在探讨MK在类风湿关节炎（RA）发病机制中的作用。采用酶联免疫吸附试验测定患者标本中MK水平，并通过免疫组化分析显示MK的定位。比较了Mdk（-/-）和野生型（WT）小鼠对抗体诱导的关节炎的易感性。破骨细胞分化的监测使用巨噬细胞样细胞分离自人类滑膜组织和巨噬细胞从小鼠骨髓。大多数RA患者血清和滑液中MK水平升高，表明MK表达与RA之间存在强相关性。MK在患者滑膜中的巨噬细胞样细胞和成纤维细胞样细胞中表达。在抗体诱导的关节炎中，Mdk（-/-）小鼠很少发生这种疾病，而大多数WT小鼠发生这种疾病。MK给药的Mdk（-/-）小鼠抗体诱导的关节炎的频率增加。在Mdk（-/-）小鼠中，疾病模型中炎性白细胞向滑膜的迁移受到抑制。MK可促进巨噬细胞向破骨细胞分化。MK参与RA发展的两个不同阶段，即炎性白细胞的迁移和破骨细胞的分化，并且是RA发病机制中的关键分子。
Objective. Midkine (MK), a heparin-binding growth factor, promotes growth, survival, and migration of various cells. The essential role of MK in migration of inflammatory cells has been shown using mice deficient in the MK gene (Mdk(-/-) mice). We undertook this study to investigate the role of MK in the pathogenesis of rheumatoid arthritis (RA).Methods. MK levels in specimens from patients were determined by enzyme-linked immunosorbent assay, and localization of MK was revealed by immunohistochemical analysis. Susceptibility to antibody-induced arthritis was compared between Mdk(-/-) and wild-type (WT) mice. Osteoclast differentiation was monitored using macrophage-like cells isolated from human synovial tissue and macrophages from mouse bone marrow.Results. MK levels in sera and synovial fluid were increased in most RA patients, indicating a strong correlation between MK expression and RA. MK was expressed in macrophage-like cells and fibroblast-like cells in synovial membranes from the patients. In antibody-induced arthritis, Mdk(-/-) mice seldom developed the disease, while most of the WT mice did. Administration of MK to the Mdk(-/-) mice increased the frequency of antibody-induced arthritis. Migration of inflammatory leukocytes to the synovial membranes in the disease model was suppressed in the Mdk(-/-) mice. Furthermore, MK was found to promote the differentiation of osteoclasts from macrophages.Conclusion. MK participates in each of the two distinct phases of RA development, namely, migration of inflammatory leukocytes and osteoclast differentiation, and is a key molecule in the pathogenesis of RA.