IBMS BoneKEy | Perspective

Notch signaling and bone

Stefano Zanotti
Ernesto Canalis

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DOI:10.1138/20110520

Abstract

The Notch receptors and their ligands, Jagged and Serrate, are transmembrane proteins that play a critical role in cell lineage specification. Notch signaling regulates skeletal development and homeostasis. Upon ligand-binding, activation of Notch canonical signaling requires cleavage of the receptor and release of the Notch intracellular domain (NICD), which translocates to the nucleus. There, it induces transcription after associating with CBF-1/RBP-Jκ, Suppressor of Hairless, Lag-2 (CSL) and Mastermind-like (MAML) proteins. Notch signaling suppresses differentiation of bone marrow mesenchymal cells and of cells committed to the osteoblastic or chondrocytic lineage. Notch induces expression of osteoprotegerin, an inhibitor of osteoclastogenesis, in osteoblastic cells. Misexpression of Hairy Enhancer of Split (Hes)1, a classic target of Notch signaling, does not phenocopy Notch misexpression in the skeleton, suggesting that other Notch target genes mediate Notch skeletal effects. In humans, aberrant Notch signaling is associated with diseases affecting skeletal development, such as Alagille syndrome, spondylocostal dysostosis and brachydactyly. JAG1 polymorphisms are associated with bone mineral density, and NOTCH2 mutations with Hajdu-Cheney syndrome. Overexpression of NOTCH1 is associated with osteosarcoma, and Notch is critical for breast cancer skeletal invasiveness. In summary, Notch suppresses the differentiation of skeletal cells and plays a role in the pathogenesis of developmental and postnatal skeletal disorders.

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