The role of Notch2-dependent signaling in skeletal remodeling

Notch信号是控制胚胎发生和成年过程中各种细胞命运决定的关键途径。它通过与四种不同的Notch受体结合的特定配体被激活，这些受体随后被早老素切割以释放进入细胞核并激活特定转录因子的细胞内结构域。虽然对激活或失活Notch信号的各种小鼠模型的骨骼分析已经证明了该途径对骨重塑的一般影响，但最近在Hajdu-Cheney综合征（HCS）患者中发现的NOTCH2突变强调了其与人类的相关性。由于HCS是一种常染色体显性遗传病，主要以骨骼缺陷为特征，这些发现促使我们分析Notch2在骨骼重塑中的具体作用。在分析了骨形成成骨细胞Notch2失活的小鼠模型（Notch2fl/fl/Runx2-Cre）之后，我们通过在小鼠Notch2基因中引入致病突变建立了HCS模型。我们观察到这些小鼠（Notch2+/HCS）表现出高骨转换表型，这可能是由成骨细胞中促破骨细胞因子的产生增加引起的，从而引发破骨细胞生成增强，进而刺激骨形成。在目前的应用中，我们打算继续分析Notch2+/HCS小鼠，以确定Notch2控制的细胞和分子机制来调节骨骼转换。

Notch signaling is a key pathway controlling various cell fate decisions during embryogenesis and adult life. It is activated by binding of specific ligands to four different Notch receptors that are subsequently cleaved by presenilins to release an intracellular domain that enters the nucleus and activates specific transcription factors. While the skeletal analysis of various mouse models with activated or inactivated Notch signaling has demonstrated a general impact of this pathway on bone remodeling, the more recent identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome (HCS) has highlighted its human relevance. Since HCS is an autosomal dominant disorder primarily characterized by skeletal defects, these latter findings led us to analyze the specific role of Notch2 in skeletal remodeling. After having analyzed a mouse model with Notch2 inactivation in bone-forming osteoblasts (Notch2fl/fl/Runx2-Cre), we established a model of HCS by introduction of a pathogenic mutation into the murine Notch2 gene. We observed that these mice (Notch2+/HCS) display a high bone turnover phenotype, potentially caused by increased production of pro-osteoclastogenic cytokines in osteoprogenitor cells, thereby triggering enhanced osteoclastogenesis, which in turn stimulates bone formation. With the present application we intend to continue our analysis of Notch2+/HCS mice in order to define the cellular and molecular mechanisms controlled by Notch2 to regulate skeletal turnover.