Enhancement of CCL2 expression and monocyte migration by CCN1 in osteoblasts through inhibiting miR-518a-5p: implication of rheumatoid arthritis therapy.
Enhancement of CCL2 expression and monocyte migration by CCN1 in osteoblasts through inhibiting miR-518a-5p: implication of rheumatoid arthritis therapy.
复制标题
DOI：
10.1038/s41598-017-00513-0
复制
发表时间：
2017-03-24
影响因子：
4.6
通讯作者：
Tang CH
中科院分区：
文献类型：
--
作者：
Chen CY;Fuh LJ;Huang CC;Hsu CJ;Su CM;Liu SC;Lin YM;Tang CH
富含半胱氨酸的61（Cyr 61或CCN 1）是来自CCN家族的分泌蛋白，是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（RA）的发病机制中起着关键作用。单核细胞趋化蛋白-1（MCP-1/CCL 2）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CCN 1在单核细胞迁移中的作用，以及CCL 2在成骨细胞中的表达。我们发现，与非RA对照组相比，RA患者滑液中CCN 1和CCL 2水平较高。我们还发现CCN 1诱导的CCL 2表达增加是由MAPK信号通路介导的，并且miR-518 a-5 p表达通过MAPK级联被CCN 1负调控。相比之下，用表达短发夹RNA的慢病毒载体抑制CCN 1表达，可改善胶原诱导性关节炎小鼠踝关节中的关节肿胀、软骨侵蚀和单核细胞浸润。我们的研究描述了CCN 1如何通过上调RA疾病成骨细胞中的CCL 2表达来促进单核细胞迁移。CCN 1可以作为RA治疗的潜在靶点。
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.