The role of Notch2-dependent signaling in skeletal remodeling

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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.