Elucidation of the molecular pathogenesis of osteoarthritis

我们试图通过使用显示骨关节炎的转基因小鼠来解决关节软骨细胞分化的分子机制。我们在体内软骨细胞中过表达缺乏QA结构域的Runx1， Runx2 （ΔQA）或Runx3（分别为α(1)II-Runx1， Runx2ΔQA或Runx3小鼠）。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在机械应力诱导的椎间盘退变小鼠模型和人类椎间盘退变患者中的表达。Runx1在间质凝聚中短暂表达，而Runx2和Runx3在肥大前软骨细胞中稳定表达。α(1)II-Runx2ΔQA和α(1)II-Runx3小鼠在α(1)II-Runx2小鼠中出现了软骨异位矿化，尽管α(1)II-Runx2ΔQA小鼠出现的程度较轻。相比之下，α(1)II-Runx1小鼠未显示异位矿化迹象。令人惊讶的是，α(1)II-Runx1和α(1)II-Runx2小鼠由于IVD变性而发生脊柱侧凸，其特征是细胞外基质的积累和异位软骨细胞肥大。在小鼠胚胎发生过程中，Runx2在IVD中表达，而Runx1和Runx3不表达。此外，在小鼠模型中，与人类IVD变性患者一样，Runx2的表达显著上调。总的来说，每个Runx在软骨细胞分化过程中具有不同但重叠的作用。Runx2参与了IVD变性的发病机制。

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.