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炎症和锌转运蛋白基因的差异性DNA甲基化和表达定义了骨关节炎髋关节患者的亚组。

Differential DNA methylation and expression of inflammatory and zinc transporter genes defines subgroups of osteoarthritic hip patients.

作者信息

Rushton Michael D, Young David A, Loughlin John, Reynard Louise N

机构信息

Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

出版信息

Ann Rheum Dis. 2015 Sep;74(9):1778-82. doi: 10.1136/annrheumdis-2014-206752. Epub 2015 Apr 8.

DOI:10.1136/annrheumdis-2014-206752
PMID:25854584
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4552898/
Abstract

OBJECTIVES

We have previously shown that the cartilage DNA methylome delineates two clusters of osteoarthritic (OA) hip patients, characterised by differential methylation of inflammatory genes, while others have demonstrated a link between zinc homeostasis and inflammation in OA. We aimed to investigate these effects at the methylation and gene expression level.

METHODS

We used our previously generated methylation data while quantitative PCR was used to measure gene expression using RNA from the hip cartilage of members of both clusters and from control individuals without hip OA.

RESULTS

One of the OA clusters is characterised by the promoter hypomethylation and increased expression of inflammation-associated genes including IL1A and TNF. Furthermore, we show that the increase in expression of these genes is accompanied by increased expression of several zinc transporter genes. In addition, the zinc responsive transcription factor MTF1 is also upregulated, which is accompanied by an increase in the expression of its targets the metalloproteinases MMP13 and ADAMTS5.

CONCLUSIONS

We have identified a subgroup of OA hip patients that are epigenetically and transcriptiomically characterised by a cartilage inflammatory phenotype with concurrent differential regulation of zinc regulators. The identification of subgroups enhances stratified phenotyping of OA patients and has important implications for future therapeutic applications.

摘要

目的

我们之前已经表明，软骨DNA甲基化组可将骨关节炎（OA）髋关节患者分为两个簇，其特征在于炎症基因的甲基化差异，而其他人则证明了锌稳态与OA炎症之间的联系。我们旨在研究甲基化和基因表达水平上的这些影响。

方法

我们使用了之前生成的甲基化数据，同时使用定量PCR来测量基因表达，所用RNA来自两个簇的成员以及无髋关节OA的对照个体的髋关节软骨。

结果

其中一个OA簇的特征是启动子低甲基化以及包括IL1A和TNF在内的炎症相关基因表达增加。此外，我们表明这些基因表达的增加伴随着几种锌转运蛋白基因表达的增加。此外，锌反应转录因子MTF1也上调，同时其靶标金属蛋白酶MMP13和ADAMTS5的表达增加。

结论

我们已经鉴定出一组OA髋关节患者亚组，其在表观遗传学和转录组学上的特征是软骨炎症表型以及锌调节因子的同时差异调节。亚组的鉴定增强了OA患者的分层表型分析，并对未来的治疗应用具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4781/4552898/6d8f54f7c316/annrheumdis-2014-206752f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4781/4552898/a2d7d7d9a2bf/annrheumdis-2014-206752f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4781/4552898/ab0fcad0c7cc/annrheumdis-2014-206752f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4781/4552898/6d8f54f7c316/annrheumdis-2014-206752f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4781/4552898/a2d7d7d9a2bf/annrheumdis-2014-206752f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4781/4552898/ab0fcad0c7cc/annrheumdis-2014-206752f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4781/4552898/6d8f54f7c316/annrheumdis-2014-206752f03.jpg

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