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Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions

机译：人骨关节炎软骨细胞基质降解酶异常表达与启动子区特异性CpG位点去甲基化的关系

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Objective. To investigate whether the abnormal expression of matrix metalloproteinases (MMPs) 3, 9, and 13 and ADAMTS-4 by human osteoarthritic (OA) chondrocytes is associated with epigenetic "unsilencing." Methods. Cartilage was obtained from the femoral heads of 16 patients with OA and 10 control patients with femoral neck fracture. Chondrocytes with abnormal enzyme expression were immunolocalized. DNA was extracted, and the methylation status of the promoter regions of MMPs 3, 9, and 13 and ADAMTS-4 was analyzed with methylation-sensitive restriction enzymes, followed by polymerase chain reaction amplification. Results. Very few chondrocytes from control cartilage expressed the degrading enzymes, whereas all clonal chondrocytes from late-stage OA cartilage were immunopositive. The overall percentage of nonmethylated sites was increased in OA patients (48.6%) compared with controls (20.1%): 20% versus 4% for MMP-13, 81% versus 47% for MMP-9, 57% versus 30% for MMP-3, and 48% versus 0% for ADAMTS-4. Not all CpG sites were equally susceptible to loss of methylation. Some sites were uniformly methylated, whereas in others, methylation was generally absent. For each enzyme, there was 1 specific CpG site where the demethylation in OA patients was significantly higher than that in controls: at -110 for MMP-13, -36 for MMP-9, -635 for MMP-3, and -753 for ADAMTS-4. Conclusion. This study provides the first evidence that altered synthesis of cartilage-degrading enzymes by late-stage OA chondrocytes may have resulted from epigenetic changes in the methylation status of CpG sites in the promoter regions of these enzymes. These changes, which are clonally transmitted to daughter cells, may contribute to the development of OA. © 2005, American College of Rheumatology.
机译：目的。调查人类骨关节炎（OA）软骨细胞基质金属蛋白酶（MMP）3、9和13和ADAMTS-4的异常表达是否与表观遗传“沉默”有关。方法。从16例OA患者和10例股骨颈骨折对照患者的股骨头中获得软骨。具有异常酶表达的软骨细胞被免疫定位。提取DNA，并使用甲基化敏感的限制性内切酶分析MMP 3、9和13和ADAMTS-4的启动子区域的甲基化状态，然后进行聚合酶链反应扩增。结果。来自对照软骨的软骨细胞很少表达降解酶，而来自晚期OA软骨的所有克隆软骨细胞都是免疫阳性的。与对照组（20.1％）相比，OA患者非甲基化位点的总体百分比（48.6％）增加：MMP-13为20％对4％，MMP-9为81％对47％，MMP为57％对30％ -3，分别为48％和ADAMTS-4的0％。并非所有的CpG位点都同样容易受到甲基化损失的影响。一些位点被一致地甲基化，而在其他位点，通常不存在甲基化。对于每种酶，都有一个特定的CpG位点，在OA患者中，其去甲基化水平明显高于对照组：MMP-13为-110，MMP-9为-36，MMP-3为-635，MMP-3为-753。 ADAMTS-4。结论。这项研究提供了第一个证据，即晚期OA软骨细胞改变软骨降解酶的合成可能是由这些酶的启动子区域CpG位点甲基化状态的表观遗传学变化引起的。这些改变被克隆地传递给子细胞，可能有助于OA的发展。 ©2005，美国风湿病学院。

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