da Silva Marco A, Yamada Norikazu, Clarke Nicholas M P, Roach Helmtrud I
Bone and Joint Research Group, University of Southampton, Southampton, United Kingdom.
J Orthop Res. 2009 May;27(5):593-601. doi: 10.1002/jor.20799.
Osteoarthritis (OA) is generally a disease of the elderly population, but can occur in young patients in exceptional cases. This study compares the cellular and epigenetic features of primary old-age OA with those of secondary OA in a 23-year-old patient with developmental dysplasia of the hip. In addition, control cartilage from a 14-year-old was compared with that from patients with a fracture of the neck of femur (#NOF) to establish to what extent the latter is a useful control for OA. Articular cartilage was obtained from discarded femoral heads after hip arthroplasty. MMP-3, MMP-9, MMP-13, and ADAMTS-4 were immunolocalized and the methylation status of specific promoter CpG sites was determined. Both primary and secondary OA were characterized by loss of aggrecan, formation of clones, and abnormal expression of the proteases that correlated with epigenetic DNA demethylation. The latter indicated that the abnormal expression of the cartilage-degrading proteases was not due to a short-term up-regulation, but a heritable, permanent alteration in gene expression. Comparing cell densities in young and old control cartilage estimated an age-related cell loss of approximately 1% per year. In aged #NOF cartilage, some superficial-zone chondrocytes expressed the proteases, but the majority of cells were immunonegative and their promoters were hypermethylated. The cellular and epigenetic features of the intermediate and deep zones of #NOF cartilage are thus similar to those of young healthy cartilage, justifying the use of #NOF cartilage as control cartilage for OA, providing the superficial zone is removed.
骨关节炎（OA）通常是一种老年疾病，但在特殊情况下也可能发生在年轻患者身上。本研究比较了一名23岁髋关节发育不良患者原发性老年OA与继发性OA的细胞和表观遗传特征。此外，将一名14岁患者的对照软骨与股骨颈骨折（#NOF）患者的软骨进行比较，以确定后者在多大程度上可作为OA的有效对照。关节软骨取自髋关节置换术后废弃的股骨头。对基质金属蛋白酶-3（MMP-3）、基质金属蛋白酶-9（MMP-9）、基质金属蛋白酶-13（MMP-13）和含血小板反应蛋白基元的解聚蛋白样金属蛋白酶-4（ADAMTS-4）进行免疫定位，并确定特定启动子CpG位点的甲基化状态。原发性和继发性OA均表现为蛋白聚糖丢失、克隆形成以及与表观遗传DNA去甲基化相关的蛋白酶异常表达。后者表明，软骨降解蛋白酶的异常表达并非由于短期上调，而是基因表达的可遗传、永久性改变。比较年轻和老年对照软骨中的细胞密度估计，每年与年龄相关的细胞损失约为1%。在老年#NOF软骨中，一些表层软骨细胞表达了这些蛋白酶，但大多数细胞免疫阴性，其启动子高度甲基化。因此，#NOF软骨中间层和深层的细胞和表观遗传特征与年轻健康软骨相似，这证明在去除表层的情况下，#NOF软骨可作为OA的对照软骨。
