Elucidation of the molecular pathogenesis of osteoarthritis

我们试图利用表现为骨关节炎的转基因小鼠来研究关节软骨细胞分化的分子机制。我们在体内软骨细胞(分别为Δ(1)II-RunX1、Runx2ΔQA或Runx3小鼠)中过表达了缺失QA结构域的Runx1和Runx2。我们用组织学和分子方法对这些小鼠进行了分析。我们还检测了RUNX在机械应力诱导的实验性小鼠椎间盘退变(IVD)模型和人类IVD退变患者中的表达。RUNX1在间质凝聚区有短暂表达，而Runx2和Runx3在肥大前期软骨细胞有强阳性表达。α(1)II-Runx2ΔQA和α(1)II-Runx3小鼠出现异位软骨矿化，α(1)II-Runx2小鼠出现虱子，而α(1)II-Runx2ΔQA小鼠表现较轻。相反，α(1)II-RUNX1小鼠没有表现出异位矿化的迹象。令人惊讶的是，α(1)II-Runx1和α(1)II-Runx2小鼠由于以细胞外基质堆积和异位软骨细胞肥大为特征的IVD变性而发展为脊柱侧弯。在小鼠胚胎发育过程中，Runx2在IVD中表达，而RUNX1或Runx3不表达。此外，在小鼠模型中，与人类IVD退行性变患者一样，Runx2的表达显著上调。总体而言，每个Runx在软骨细胞分化过程中都有不同但重叠的作用。Runx2参与了IVD退行性变的发病机制。

We tried to address the molecular mechanism of the articular chondrocyte differentiation by using transgenic mice that display osteoarthritis. We overexpressed Runx1, Runx2 lacking the QA domain (ΔQA) or Runx3 in chondrocytes in vivo (α(1)II-Runx1, Runx2ΔQA or Runx3 mice, respectively). We analyzed these mice using histological and molecular methods. We also examined Runx expression in an experimental mouse model of mechanical stress-induced intervertebral disc (IVD) degeneration and in human patients with IVD degeneration. Runx1 expression was transiently observed in mesenchymal condensations, while Runx2 and Runx3 were robustly expressed in prehypertrophic chondrocytes. α(1)II-Runx2ΔQA and α(1)II-Runx3 mice developed ectopic mineralization of cartilage, lice in α(1)II-Runx2 mice, although α(1)II-Runx2ΔQA mice exhibited to a lesser extent. In contrast, α(1)II-Runx1 mice displayed no sign of ectopic mineralization. Surprisingly, α(1)II-Runx1 and α(1)II-Runx2 mice developed scoliosis due to IVD degeneration characterized by an accumulation of extracellular matrix and ectopic chondrocyte hypertrophy. During mouse embryogenesis, Runx2, but not Runx1 or Runx3, was expressed in the IVD. Moreover, in a mouse model, as in human patients with IVD degeneration, there was significant upregulation of Runx2 expression.Collectively, Each Runx has a distinct yet overlapping role during chondrocyte differentiation. Runx2 contributes to the pathogenesis of IVD degeneration.