Research of Notch signal in pathophysiology and therapeutics of osteoarthritis

Notch信号通路由5种配体和4种受体（Notch 1 -4）组成。在配体结合后，Notch受体被切割并且其胞内结构域（ICD）易位到细胞核，在那里它结合到转录阻遏物Rbpj，并且激活靶基因（包括Hes/Hey家族成员）的表达。Notch 1和Notch 2在小鼠和人关节软骨细胞中表达，并且它们的ICD随着软骨降解移位到细胞核。当我们使用他莫昔芬诱导的Cre小鼠在骨骼生长后删除软骨细胞中的Rbpj并创建实验性OA模型时，软骨降解和Mmp 13表达受到抑制。我们使用Hes 1-flox小鼠进一步研究了Hes 1的功能，Hes 1是唯一在软骨细胞中大量表达的靶基因。当我们以同样的方式删除Hes 1时，OA的发展受到抑制，而骨骼发育不受影响。

Notch signaling consists of 5 ligands and 4 receptors (Notch1-4). Upon ligand binding, the Notch receptor is cleaved and its intracellular domain (ICD) translocates to the nucleus, where it binds to Rbpj, a transcription repressor, and activates expression of target genes including Hes/Hey family member. Notch1 and 2 were expressed in mouse and human articular chondrocytes, and their ICDs were translocated to the nucleus with cartilage degradation. When we deleted Rbpj in chondrocytes after skeletal growth using tamoxifen-inducible Cre mice and created an experimental OA model, cartilage degradation and Mmp13 expression were suppressed. We further investigated functions of Hes1, only target gene expressed abundantly in chondrocytes, using Hes1-flox mice. When we deleted Hes1 in the same way, OA development was suppressed while skeletal development was not affected.