全基因组 DNA 甲基化研究鉴定出骨关节炎软骨下骨中显著的表观基因组变化，并与覆盖的软骨具有相似性。
Genome-Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Subchondral Bone and Similarity to Overlying Cartilage.
机构信息
University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation, Oklahoma City.
Oklahoma Medical Research Foundation, Oklahoma City.
出版信息
Arthritis Rheumatol. 2016 Jun;68(6):1403-14. doi: 10.1002/art.39555.
OBJECTIVE
To perform a genome-wide DNA methylation study to identify differential DNA methylation patterns in subchondral bone underlying eroded and intact cartilage from patients with hip osteoarthritis (OA) and to compare these with DNA methylation patterns in overlying cartilage.
METHODS
Genome-wide DNA methylation profiling using Illumina HumanMethylation 450 arrays was performed on eroded and intact cartilage and subchondral bone from within the same joint of 12 patients undergoing hip arthroplasty. Genes with differentially methylated CpG sites were analyzed to identify shared pathways, upstream regulators, and overrepresented gene ontologies, and these patterns were compared with those of the overlying cartilage. Histopathology was graded by modified Mankin score and assessed for correlation with DNA methylation.
RESULTS
We identified 7,316 differentially methylated CpG sites in subchondral bone underlying eroded cartilage, most of which (∼75%) were hypomethylated, and 1,397 sites in overlying eroded cartilage, 126 of which were shared. Samples clustered into 3 groups with distinct histopathologic scores. We observed differential DNA methylation of genes including the RNA interference-processing gene AGO2, the growth factor TGFB3, the OA suppressor NFATC1, and the epigenetic effector HDAC4. Among known susceptibility genes in OA, 32 were differentially methylated in subchondral bone, 8 were differentially methylated in cartilage, and 5 were shared. Upstream regulator analysis using differentially methylated genes in OA subchondral bone showed a strong transforming growth factor β1 signature (P = 1 × 10(-40) ) and a tumor necrosis factor family signature (P = 3.2 × 10(-28) ), among others.
CONCLUSION
Our data suggest the presence of an epigenetic phenotype associated with eroded OA subchondral bone that is similar to that of overlying eroded OA cartilage.
目的
进行全基因组 DNA 甲基化研究，以鉴定髋骨关节炎（OA）患者侵蚀性和完整软骨下骨中的差异 DNA 甲基化模式，并将这些模式与覆盖软骨的 DNA 甲基化模式进行比较。
方法
对 12 名接受髋关节置换术的患者同一关节内的侵蚀性和完整软骨及软骨下骨进行全基因组 DNA 甲基化谱分析，采用 Illumina HumanMethylation 450 阵列。对具有差异甲基化 CpG 位点的基因进行分析，以识别共同途径、上游调节剂和过度表达的基因本体论，并将这些模式与覆盖软骨的模式进行比较。通过改良的 Mankin 评分对组织病理学进行分级，并评估与 DNA 甲基化的相关性。
结果
我们在侵蚀性软骨下骨中鉴定出 7316 个差异甲基化 CpG 位点，其中大多数（约 75%）呈低甲基化，在侵蚀性覆盖软骨中鉴定出 1397 个位点，其中 126 个位点是共同的。样本聚类为具有明显组织病理学评分的 3 个组。我们观察到包括 RNA 干扰处理基因 AGO2、生长因子 TGFB3、OA 抑制因子 NFATC1 和表观遗传效应因子 HDAC4 在内的基因的 DNA 甲基化差异。在 OA 中的已知易感基因中，32 个在软骨下骨中差异甲基化，8 个在软骨中差异甲基化，5 个是共同的。使用 OA 软骨下骨中差异甲基化基因进行的上游调节剂分析显示，转化生长因子 β1 特征（P=1×10(-40)）和肿瘤坏死因子家族特征（P=3.2×10(-28)）等特征非常强烈。
结论
我们的数据表明，存在与侵蚀性 OA 软骨下骨相关的表观遗传表型，与覆盖的侵蚀性 OA 软骨相似。
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