Kennedy Institute of Rheumatology, University of Oxford, 65 Aspenlea Road, London W6 8LH, United Kingdom.
J Biol Chem. 2012 Jan 6;287(2):916-24. doi: 10.1074/jbc.M111.302430. Epub 2011 Nov 18.
Articular cartilage enables weight bearing and near friction-free movement in the joints. Critical to its function is the production of a specialized, mechanocompetent extracellular matrix controlled by master regulator transcription factor SOX9. Mutations in SOX9 cause campomelic dysplasia, a haploinsufficiency disorder resulting in severe skeletal defects and dwarfism. Although much is understood about how SOX9 regulates cartilage matrix synthesis and hence joint function, how this master regulator is itself regulated remains largely unknown. Here we identify a specific microRNA, miR-145, as a direct regulator of SOX9 in normal healthy human articular chondrocytes. We show that miR-145 directly represses SOX9 expression in human cells through a unique binding site in its 3'-UTR not conserved in mice. Modulation of miR-145 induced profound changes in the human chondrocyte phenotype. Specifically, increased miR-145 levels cause greatly reduced expression of critical cartilage extracellular matrix genes (COL2A1 and aggrecan) and tissue-specific microRNAs (miR-675 and miR-140) and increased levels of the hypertrophic markers RUNX2 and MMP13, characteristic of changes occurring in osteoarthritis. We propose miR-145 as an important regulator of human chondrocyte function and a new target for cartilage repair.
关节软骨使关节能够承重并实现近乎无摩擦的运动。其功能的关键是产生一种特殊的、机械适应的细胞外基质，由主调控转录因子 SOX9 控制。SOX9 基因突变会导致卡梅隆综合征，这是一种半合子不足的疾病，导致严重的骨骼缺陷和侏儒症。尽管人们已经了解 SOX9 如何调节软骨基质合成从而影响关节功能，但该主调控因子本身如何被调控在很大程度上仍不清楚。在这里，我们鉴定出一种特定的 microRNA，miR-145，是正常健康人关节软骨细胞中 SOX9 的直接调控因子。我们表明，miR-145 通过其 3'-UTR 中的一个独特结合位点直接抑制人细胞中的 SOX9 表达，而该结合位点在小鼠中没有保守。miR-145 的调节会引起人软骨细胞表型的深刻变化。具体而言，miR-145 水平的增加会导致关键软骨细胞外基质基因（COL2A1 和 aggrecan）和组织特异性 microRNAs（miR-675 和 miR-140）的表达大大降低，同时会导致肥大标志物 RUNX2 和 MMP13 的水平升高，这是骨关节炎中发生的变化的特征。我们提出 miR-145 是人类软骨细胞功能的重要调节剂，也是软骨修复的新靶点。
