Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Department of Prosthodontics, China Medical University Hospital, Taichung, Taiwan.
Sci Rep. 2017 Mar 24;7(1):421. doi: 10.1038/s41598-017-00513-0.
Cysteine-rich 61 (Cyr61 or CCN1), a secreted protein from the CCN family, is an important proinflammatory cytokine. Migration and infiltration of mononuclear cells to inflammatory sites play a critical role in the pathogenesis of rheumatoid arthritis (RA). Monocyte chemoattractant protein-1 (MCP-1/CCL2) is the key chemokine that regulates migration and infiltration of monocytes. Here, we examined the role of CCN1 in monocyte migration, and CCL2 expression in osteoblasts. We found higher levels of CCN1 and CCL2 in synovial fluid from RA patients compared with levels from non-RA controls. We also found that the CCN1-induced increase in CCL2 expression is mediated by the MAPK signaling pathway and that miR-518a-5p expression was negatively regulated by CCN1 via the MAPK cascade. In contrast, inhibition of CCN1 expression with lentiviral vectors expressing short hairpin RNA ameliorated articular swelling, cartilage erosion, and infiltration of monocytes in the ankle joints of mice with collagen-induced arthritis. Our study describes how CCN1 promotes monocyte migration by upregulating CCL2 expression in osteoblasts in RA disease. CCN1 could serve as a potential target for RA treatment.
富含半胱氨酸的 61 型（Cysteine-rich 61，Cyr61 或 CCN1）是一种来自 CCN 家族的分泌蛋白，是一种重要的促炎细胞因子。单核细胞向炎症部位的迁移和浸润在类风湿关节炎（rheumatoid arthritis，RA）的发病机制中起着关键作用。单核细胞趋化蛋白-1（monocyte chemoattractant protein-1，MCP-1/CCL2）是调节单核细胞迁移和浸润的关键趋化因子。在这里，我们研究了 CCN1 在单核细胞迁移和破骨细胞中 CCL2 表达中的作用。我们发现 RA 患者的滑液中 CCN1 和 CCL2 的水平高于非 RA 对照组。我们还发现，CCN1 诱导的 CCL2 表达增加是通过 MAPK 信号通路介导的，而 miR-518a-5p 的表达通过 MAPK 级联被 CCN1 负调控。相反，用表达短发夹 RNA 的慢病毒载体抑制 CCN1 表达可改善胶原诱导性关节炎小鼠踝关节的关节肿胀、软骨侵蚀和单核细胞浸润。我们的研究描述了 CCN1 如何通过上调破骨细胞中 CCL2 的表达来促进 RA 疾病中的单核细胞迁移。CCN1 可能成为 RA 治疗的潜在靶点。
