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SPARC 基因的 DNA 甲基化与慢性下腰痛。

DNA methylation of SPARC and chronic low back pain.

机构信息

Alan Edwards Centre for Research on Pain, McGill University, 740 Dr, Penfield Avenue, Montreal, Quebec, H3A 1A4, Canada.

出版信息

Mol Pain. 2011 Aug 25;7:65. doi: 10.1186/1744-8069-7-65.

DOI:10.1186/1744-8069-7-65
PMID:21867537
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3182907/
Abstract

BACKGROUND

The extracellular matrix protein SPARC (Secreted Protein, Acidic, Rich in Cysteine) has been linked to degeneration of the intervertebral discs and chronic low back pain (LBP). In humans, SPARC protein expression is decreased as a function of age and disc degeneration. In mice, inactivation of the SPARC gene results in the development of accelerated age-dependent disc degeneration concurrent with age-dependent behavioral signs of chronic LBP.DNA methylation is the covalent modification of DNA by addition of methyl moieties to cytosines in DNA. DNA methylation plays an important role in programming of gene expression, including in the dynamic regulation of changes in gene expression in response to aging and environmental signals. We tested the hypothesis that DNA methylation down-regulates SPARC expression in chronic LBP in pre-clinical models and in patients with chronic LBP.

RESULTS

Our data shows that aging mice develop anatomical and behavioral signs of disc degeneration and back pain, decreased SPARC expression and increased methylation of the SPARC promoter. In parallel, we show that human subjects with back pain exhibit signs of disc degeneration and increased methylation of the SPARC promoter. Methylation of either the human or mouse SPARC promoter silences its activity in transient transfection assays.

CONCLUSIONS

This study provides the first evidence that DNA methylation of a single gene plays a role in chronic pain in humans and animal models. This has important implications for understanding the mechanisms involved in chronic pain and for pain therapy.

摘要

背景

细胞外基质蛋白 SPARC（富含半胱氨酸的酸性分泌蛋白）与椎间盘退变和慢性下腰痛（LBP）有关。在人类中，SPARC 蛋白的表达随着年龄的增长和椎间盘退变而减少。在小鼠中，SPARC 基因的失活导致加速的年龄依赖性椎间盘退变与年龄依赖性慢性 LBP 的行为迹象同时发生。DNA 甲基化是 DNA 上的碱基通过添加甲基基团而发生的共价修饰。DNA 甲基化在基因表达的编程中起着重要作用，包括对衰老和环境信号引起的基因表达变化的动态调控。我们检验了以下假设，即 DNA 甲基化会下调慢性 LBP 中小鼠和患者的 SPARC 表达。

结果

我们的数据表明，衰老的小鼠会出现椎间盘退变和腰痛的解剖学和行为学迹象，SPARC 表达降低，SPARC 启动子的甲基化增加。同时，我们发现腰痛患者的 SPARC 启动子存在退行性变和甲基化增加的迹象。人或鼠 SPARC 启动子的甲基化会使其在瞬时转染试验中沉默其活性。

结论

本研究首次提供了证据表明，单个基因的 DNA 甲基化在人类和动物模型的慢性疼痛中起作用。这对于理解慢性疼痛涉及的机制以及疼痛治疗具有重要意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/146c5169d2b9/1744-8069-7-65-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/6849a157095a/1744-8069-7-65-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/62f6a497b317/1744-8069-7-65-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/1b4f08f0f1ee/1744-8069-7-65-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/803e4c09a698/1744-8069-7-65-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/146c5169d2b9/1744-8069-7-65-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/6849a157095a/1744-8069-7-65-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/62f6a497b317/1744-8069-7-65-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/1b4f08f0f1ee/1744-8069-7-65-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/803e4c09a698/1744-8069-7-65-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9fe4/3182907/146c5169d2b9/1744-8069-7-65-5.jpg

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