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Osteoporosis International

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

Notch in skeletal physiology and disease

  • E. CanalisEmail author
Review Article

Abstract

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.

Keywords

Congenital disorders Jagged Notch Osteoblast Osteoclast 

Abbreviations

ANK

ankyrin

BMD

bone mineral density

CHSY

chondroitin sulfate synthase

DII

Delta-like

Dkk1

Dickkopf 1

EGF

epidermal growth factor

HES

hairy and enhancer of split

EOGT

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

HCS

Hajdu-Cheney syndrome

HEY

HES with a YRPW motif

HD

heterodimerization domain

Jag

jagged

MAML

mastermind-like

LP

leader peptide

LMS

lateral meningocele syndrome

LNR

Lin12-Notch repeats

Lnfg

lunatic fringe

NRR

negative regulatory region

NICD

Notch intracellular domain

Nf

nuclear factor

NLS

nuclear localization sequence

PTH

parathyroid hormone

PEST

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

RANKL

receptor activator of NF-κB ligand

RBPJκ

recombination signal-binding protein for Ig of κ region

RAM

RBPJκ-association module

TGF

transforming growth factor

TMD

transmembrane domain

Notes

Acknowledgments

The author thanks Mary Yurczak for secretarial assistance.

Funding

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

None.

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Copyright information

© 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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