Inflammation-dependent downregulation of miR-194-5p contributes to human intervertebral disc degeneration by targeting CUL4A and CUL4B
Inflammation-dependent downregulation of miR-194-5p contributes to human intervertebral disc degeneration by targeting CUL4A and CUL4B
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miR-194-5p 的炎症依赖性下调通过靶向 CUL4A 和 CUL4B 导致人椎间盘退变
DOI：
10.1002/jcp.28595
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Qian, Lie
中科院分区：
文献类型：
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作者：
Chen, Zhi;Han, Yingchao;Qian, Lie
炎症是椎间盘退变（IDD）的主要原因之一。新出现的证据表明，促炎细胞因子（如白细胞介素6（IL-6）和肿瘤坏死因子α（TNF-α））水平的增加可激活多种信号通路，最终导致IDD。在这里，我们表明，两个cullin家族基因，CUL 4A和CUL 4 B，而不是其他cullin，是特异性过表达的IDD样品相比，健康对照组，和CUL 4A和CUL 4 B水平与IDD的严重程度呈正相关。对人成骨细胞（hFOB1.19）、髓核细胞（hNPC）和纤维环细胞（hAFC）的体外分析表明，IL-6和TNF-α处理可以增加CUL 4A和CUL 4 B水平。通过进行基于microRNA的微阵列分析，我们发现了一组microRNA（miRNAs）在IDD样本中与健康对照样本相比差异表达。在这些miRNA中，miR-194- 5 p在IDD样品中显著下调，并且可以结合CUL 4A和CUL 4 B的三个主要非翻译区（3 '-UTR），从而下调它们的表达。用miR-194 - 5 p模拟物或用抗miR-194 - 5 p体外过表达或下调miR-194- 5 p可分别引起CUL 4A和CUL 4 B的抑制或诱导。有趣的是，在从IDD患者分离的原代hNPC和hAFC中用IL-6和TNF-α抑制剂治疗导致CUL 4A和CUL 4 B的下调。总之，这些发现提供了对miR-194- 5 p的炎症依赖性下调如何有助于IDD发病机制的深入了解，这可能有助于通过直接靶向miR-194- 5 p或CUL 4A和CUL 4 B开发IDD的新治疗方法。
Inflammation is one of the major causes of intervertebral disc degeneration (IDD). Emerging evidence has revealed that increase in the levels of pro-inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), can activate a variety of signaling pathways, eventually resulting in IDD. Here, we show that the two cullin family genes, CUL4A and CUL4B, but not other cullins, are specifically overexpressed in IDD samples compared with healthy controls, and the CUL4A and CUL4B levels are positively correlated with the severity of IDD. In vitro analyses in human osteoblast cells (hFOB1.19), nucleus pulposus cells (hNPCs), and annulus fibrosus cells (hAFCs) indicated that treatment with IL-6 and TNF-alpha can increase CUL4A and CUL4B levels. By performing a microRNA-based microarray analysis, we found a set of microRNAs (miRNAs) that were differentially expressed in IDD samples compared with samples from healthy controls. Of these miRNAs, miR-194-5p, was significantly downregulated in IDD samples and could bind to the three prime untranslated regions (3 '-UTRs) of both CUL4A and CUL4B, thereby downregulating their expression. The in vitro overexpression or downregulation of miR-194-5p, with a miR-194-5p-mimic or with anti-miR-194-5p, can cause the repression or induction of both CUL4A and CUL4B, respectively. Interestingly, treatment with IL-6 and TNF-alpha inhibitors in primary hNPCs and hAFCs that were isolated from patients with IDD led to the downregulation of CUL4A and CUL4B. Together, these findings provide insight into how the inflammation-dependent downregulation of miR-194-5p contributes to the pathogenesis of IDD, which may aid in the development of new therapeutic approaches for IDD by directly targeting miR-194-5p or CUL4A and CUL4B.