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Notch in skeletal physiology and disease

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A Correction to this article was published on 19 October 2018

This article has been updated

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.

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Change history

  • 19 October 2018

    Table 2 of the original article was incorrect. The correct table is shown below.

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

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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.

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  1. Departments of Orthopaedic Surgery and Medicine, UConn Musculoskeletal Institute, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030-4037, USA

    E. Canalis

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Correspondence to E. Canalis.

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Canalis, E. Notch in skeletal physiology and disease. Osteoporos Int 29, 2611–2621 (2018). https://doi.org/10.1007/s00198-018-4694-3

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  • DOI: https://doi.org/10.1007/s00198-018-4694-3

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