The IL-1β/AP-1/miR-30a/ADAMTS-5 axis regulates cartilage matrix degradation in human osteoarthritis
The IL-1β/AP-1/miR-30a/ADAMTS-5 axis regulates cartilage matrix degradation in human osteoarthritis
复制标题
IL-1β/AP-1/miR-30a/ADAMTS-5 轴调节人类骨关节炎的软骨基质降解
DOI：
10.1007/s00109-016-1418-z
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发表时间：
2016-07-01
影响因子：
4.7
通讯作者：
Wang, Yan
中科院分区：
文献类型：
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作者：
Ji, Quanbo;Xu, Xiaojie;Wang, Yan
促炎细胞因子白细胞介素 1 β (IL-1 β) 通过刺激基质降解蛋白酶的表达参与骨关节炎 (OA) 的起始和进展，例如具有血小板反应蛋白基序 5 的解整合素金属蛋白酶 (ADAMTS-5)，它是 OA 发病机制的关键参与者。然而，人们对 IL-1 beta 如何诱导 ADAMTS-5 过度表达知之甚少。我们证明 IL-1 beta 通过抑制 microRNA-30a (miR-30a) 来调节 ADAMTS-5 表达。通过生物信息学预测靶向 ADAMTS-5 的 miRNA。 miR-30a 通过直接靶向 ADAMTS-5 的 3'-非翻译区来抑制 ADAMTS-5 的表达。 miR-30a 表达在 OA 患者中下调，与 ADAMTS-5 表达呈负相关，与特种外科医院 (HSS) 评分呈正相关。 IL-1 beta 通过将激活蛋白 (AP-1) 转录因子 c-jun/c-fos 招募到 miR-30a 启动子来抑制 miR-30a 表达。 IL-1 beta 诱导的 c-jun/c-fos 表达通过人软骨细胞中的 miR-30a 调节 ADAMTS-5 表达和软骨基质降解。这些数据表明，IL-1β/AP-1/miR-30a/ADAMTS-5 途径有助于 IL-1β 诱导人 OA 软骨细胞中的软骨基质降解。 miR-30a 可能作为软骨稳态的关键调节剂和 OA 的潜在诊断和治疗靶点。IL-1 beta 通过激活 AP-1 (c-jun/c-fos) 抑制 miR-30a 表达。AP-1/miR-30a 对于 OA 中 IL-1 beta 诱导的 ADAMTS-5 上调至关重要。OA 中 miR-30a 的下调与 ADAMTS-5 呈负相关表达。
The proinflammatory cytokine interleukin-1 beta (IL-1 beta) is involved in the initiation and progression of osteoarthritis (OA) by stimulating the expression of matrix-degrading proteinases, such as a disintegrin metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), a key player in OA pathogenesis. However, how IL-1 beta induces ADAMTS-5 overexpression is poorly understood. We demonstrate that IL-1 beta regulates ADAMTS-5 expression by suppressing microRNA-30a (miR-30a). Bioinformatics was performed to predict miRNAs targeting ADAMTS-5. miR-30a inhibited ADAMTS-5 expression by directly targeting its 3'-untranslated region. miR-30a expression was downregulated in OA patients and was negatively correlated with ADAMTS-5 expression and positively correlated with Hospital for Special Surgery (HSS) scores. IL-1 beta suppressed miR-30a expression by recruiting the activator protein (AP-1) transcription factor c-jun/c-fos to the miR-30a promoter. IL-1 beta-induced c-jun/c-fos expression regulated ADAMTS-5 expression and cartilage matrix degradation via miR-30a in human chondrocytes. These data indicate that the IL-1 beta/AP-1/miR-30a/ADAMTS-5 pathway contributes to IL-1 beta-induced cartilage matrix degradation in human OA chondrocytes. miR-30a may act as a pivotal regulator of cartilage homeostasis and a potential diagnostic and therapeutic target for OA.IL-1 beta suppresses miR-30a expression through activation of AP-1 (c-jun/c-fos).AP-1/miR-30a is essential for IL-1 beta-induced ADAMTS-5 upregulation in OA.Downregulation of miR-30a in OA is negatively correlated with ADAMTS-5 expression.