Osteoporosis International

, Volume 29, Issue 12, pp 2611–2621 | Cite as

Notch in skeletal physiology and disease

  • E. CanalisEmail author
Review Article


Notch (Notch1 through 4) are transmembrane receptors that play a fundamental role in cell differentiation and function. Notch receptors are activated following interactions with their ligands in neighboring cells. There are five classic ligands termed Jagged (Jag)1 and Jag2 and Delta-like (Dll)1, Dll3, and Dll4. Recent work has established Notch as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages and in skeletal development and bone remodeling. The effects of Notch are cell-context dependent, and the four Notch receptors carry out specific functions in the skeleton. Gain- and loss-of-function mutations of components of the Notch signaling pathway result in a variety of congenital disorders with significant craniofacial and skeletal manifestations. The Notch ligand Jag1 is a determinant of bone mineral density, and Notch plays a role in the early phases of fracture healing. Alterations in Notch signaling are associated with osteosarcoma and with the metastatic potential of carcinoma of the breast and of the prostate. Controlling Notch signaling could prove useful in diseases of Notch gain-of-function and in selected skeletal disorders. However, clinical data on agents that modify Notch signaling are not available. In conclusion, Notch signaling is a novel pathway that regulates skeletal homeostasis in health and disease.


Congenital disorders Jagged Notch Osteoblast Osteoclast 





bone mineral density


chondroitin sulfate synthase




Dickkopf 1


epidermal growth factor


hairy and enhancer of split


EGF-domain-specific O-linked N-acetylglucosamine transferase


Hajdu-Cheney syndrome


HES with a YRPW motif


heterodimerization domain






leader peptide


lateral meningocele syndrome


Lin12-Notch repeats


lunatic fringe


negative regulatory region


Notch intracellular domain


nuclear factor


nuclear localization sequence


parathyroid hormone


proline (P)-, glutamic acid (E)-, serine (S)-, and threonine (T)-rich


receptor activator of NF-κB ligand


recombination signal-binding protein for Ig of κ region


RBPJκ-association module


transforming growth factor


transmembrane domain



The author thanks Mary Yurczak for secretarial assistance.


This work was supported by Grants AR063049, AR068160, and AR072987 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and Grant DK045227 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Compliance with ethical standards

Conflicts of interest



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© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  1. 1.Departments of Orthopaedic Surgery and Medicine, UConn Musculoskeletal InstituteUConn HealthFarmingtonUSA

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