School of Medicine, China Medical University, Taichung, Taiwan; Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Biochim Biophys Acta Gen Subj. 2017 Feb;1861(2):15-22. doi: 10.1016/j.bbagen.2016.11.015. Epub 2016 Nov 13.
Osteopontin (OPN) is an important proinflammatory cytokine in rheumatoid arthritis (RA). Levels of OPN have been shown to be significantly correlated with interleukin-17 (IL-17) production and expression of Th17 cells in the synovial fluid of RA patients. Here, we investigated the role of OPN in monocyte migration, IL-17 production and osteoblasts.
OPN and IL-17 expression profiles in osteoarthritis (OA) and RA synovial fluid were determined by enzyme-linked immunosorbent assay (ELISA). The expression of the microRNA, miR-129-3p, in osteoblasts was analyzed by real-time quantitative polymerase chain reaction (qPCR). Immunoreactive proteins were spotted by Western blotting. We used the collagen-induced arthritis (CIA) mouse model to investigate the role of OPN in monocyte migration during RA.
OPN and IL-17 expression were higher in RA synovial fluid as compared to OA samples. We also found that OPN promotes IL-17 expression in osteoblasts and thereby enhances monocyte migration via the Syk/PI3K/Akt signaling pathway. miR-129-3p expression was found to be negatively regulated by OPN via the Syk/PI3K/Akt signal cascade. In contrast, lentiviral vectors expressing short hairpin RNA inhibited OPN expression and ameliorated articular swelling, cartilage erosion and monocyte infiltration in the ankle joints of CIA mice.
To our knowledge, our study is the first to describe how OPN promotes monocyte migration by upregulating IL-17 expression in osteoblasts in RA disease.
These findings indicate that OPN could serve as a potential therapeutic target for the treatment of RA.
骨桥蛋白 (OPN) 是类风湿关节炎 (RA) 中的一种重要促炎细胞因子。研究表明，OPN 水平与 RA 患者滑液中白细胞介素-17 (IL-17) 的产生和 Th17 细胞的表达显著相关。在这里，我们研究了 OPN 在单核细胞迁移、IL-17 产生和破骨细胞中的作用。
通过酶联免疫吸附试验 (ELISA) 测定骨关节炎 (OA) 和 RA 滑液中 OPN 和 IL-17 的表达谱。通过实时定量聚合酶链反应 (qPCR) 分析成骨细胞中 microRNA，miR-129-3p 的表达。通过 Western 印迹检测免疫反应性蛋白。我们使用胶原诱导性关节炎 (CIA) 小鼠模型来研究 OPN 在 RA 期间单核细胞迁移中的作用。
与 OA 样本相比，RA 滑液中 OPN 和 IL-17 的表达更高。我们还发现 OPN 促进成骨细胞中 IL-17 的表达，从而通过 Syk/PI3K/Akt 信号通路增强单核细胞迁移。miR-129-3p 的表达通过 Syk/PI3K/Akt 信号级联被发现受到 OPN 的负调控。相反，表达短发夹 RNA 的慢病毒载体抑制 OPN 表达并改善 CIA 小鼠踝关节的关节肿胀、软骨侵蚀和单核细胞浸润。
据我们所知，我们的研究首次描述了 OPN 如何通过上调成骨细胞中 IL-17 的表达来促进 RA 疾病中的单核细胞迁移。
这些发现表明 OPN 可以作为治疗 RA 的潜在治疗靶点。
