Notch signaling in skeletal health and disease.

Notch receptors are single-pass transmembrane proteins that determine cell fate. Upon Notch ligand interactions, proteolytic cleavages release the Notch intracellular domain, which translocates to the nucleus to regulate the transcription of target genes, including Hairy enhancer of split (Hes) and Hes related to YRPW motif (Hey). Notch is critical for skeletal development and activity of skeletal cells, and dysregulation of Notch signaling is associated with human diseases affecting the skeleton. Inherited or sporadic mutations in components of the Notch signaling pathway are associated with spondylocostal dysostosis, spondylothoracic dysostosis and recessive brachydactyly, diseases characterized by skeletal patterning defects. Inactivating mutations of the Notch ligand JAG1 or of NOTCH2 are associated with Alagille syndrome, and activating mutations in NOTCH2 are associated with Hajdu-Cheney syndrome (HCS). Individuals affected by HCS exhibit osteolysis in distal phalanges and osteoporosis. NOTCH is activated in selected tumors, such as osteosarcoma, and in breast cancer cells that form osteolytic bone metastases. In conclusion, Notch regulates skeletal development and bone remodeling, and gain- or loss-of-function mutations of Notch signaling result in important skeletal diseases.
AuthorsStefano Zanotti, Ernesto Canalis
JournalEuropean journal of endocrinology / European Federation of Endocrine Societies (Eur J Endocrinol) Vol. 168 Issue 6 Pg. R95-103 (Jun 2013) ISSN: 1479-683X [Electronic] England
PMID23554451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Receptors, Notch
  • Animals
  • Bone Remodeling
  • Bone and Bones (metabolism, pathology)
  • Humans
  • Receptors, Notch (genetics, metabolism)
  • Signal Transduction (genetics, physiology)

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