Skip to main content
SpringerLink
Log in

Notch Signaling and Bone Remodeling

  • Skeletal Regulations (D Gaddy, Section Editor)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Notch signaling plays context-dependent roles in the development and maintenance of many cell types and tissues in mammals. In the skeleton, both osteoblasts and osteoclasts require Notch signaling for proper differentiation and function, and the specific roles of Notch are dependent on the differentiation status of the cell. The recent discovery of activating NOTCH2 mutations as the cause of Hajdu-Cheney syndrome has highlighted the significance of Notch signaling in human bone physiology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137:216–33.

    Article  PubMed  Google Scholar 

  2. Fortini ME. Notch signaling: the core pathway and its posttranslational regulation. Dev Cell. 2009;16:633–47.

    Article  PubMed  Google Scholar 

  3. Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design, versatility in function. Development. 2011;138:3593–612.

    Article  PubMed  Google Scholar 

  4. Canalis E. Notch signaling in osteoblasts. Sci Signal. 2008;1:17.

    Article  Google Scholar 

  5. Deregowski V, Gazzerro E, Priest L, Rydziel S, Canalis E. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signaling. J Biol Chem. 2006;281:6203–10.

    Article  PubMed  Google Scholar 

  6. • Sciaudone M, Gazzerro E, Priest L, Delany AM, Canalis E. Notch 1 impairs osteoblastic cell differentiation. Endocrinology. 2003;144:5631–9. An early in vitro study demonstrating a suppresive role for Notch signaling in osteoblast differentiation.

    Article  PubMed  Google Scholar 

  7. Tezuka K, Yasuda M, Watanabe N, et al. Stimulation of osteoblastic cell differentiation by Notch. J Bone Miner Res. 2002;17:231–9.

    Article  PubMed  Google Scholar 

  8. Nobta M, Tsukazaki T, Shibata Y, et al. Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. J Biol Chem. 2005;280:15842–8.

    Article  PubMed  Google Scholar 

  9. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997;89:629–39.

    Article  PubMed  Google Scholar 

  10. Wong PC, Zheng H, Chen H, et al. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997;387:288–92.

    Article  PubMed  Google Scholar 

  11. Dunwoodie SL, Clements M, Sparrow DB, Sa X, Conlon RA, Beddington RS. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development. 2002;129:1795–806.

    PubMed  Google Scholar 

  12. • Hilton MJ, Tu X, Wu X, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008;14:306–14. This mouse genetic study establishes that physiological Notch singaling suppresses bone formation in vivo.

    Article  PubMed  Google Scholar 

  13. • Tu X, Chen J, Lim J, et al. Physiological notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1. PLoS Genet. 2012;8:e1002577. This study delineates the mechanism through which physiological Notch signaling suppresses bone formation, and identifies Notch2 as a critical regulator.

    Article  PubMed  Google Scholar 

  14. Salie R, Kneissel M, Vukevic M, et al. Ubiquitous overexpression of Hey1 transcription factor leads to osteopenia and chondrocyte hypertrophy in bone. Bone. 2010;46:680–94.

    Article  PubMed  Google Scholar 

  15. Engin F, Yao Z, Yang T, et al. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med. 2008;14:299–305.

    Article  PubMed  Google Scholar 

  16. • Tao J, Chen S, Yang T, et al. Osteosclerosis owing to Notch gain of function is solely Rbpj-dependent. J Bone Miner Res. 2010;25:2175–83. These two mouse genetic studies demonstrate that hyperactivation of Notch signaling through RBPj impairs bone homeostasis.

    Article  PubMed  Google Scholar 

  17. Zanotti S, Smerdel-Ramoya A, Stadmeyer L, Durant D, Radtke F, Canalis E. Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology. 2008;149:3890–9.

    Article  PubMed  Google Scholar 

  18. Murtaugh LC, Stanger BZ, Kwan KM, Melton DA. Notch signaling controls multiple steps of pancreatic differentiation. Proc Natl Acad Sci U S A. 2003;100:14920–5.

    Article  PubMed  Google Scholar 

  19. • Canalis E, Parker K, Feng JQ, Zanotti S. Osteoblast lineage-specific effects of Notch activation in the skeleton. Endocrinology. 2013;154(2):623–34. This study highlights the stage-specific effects of hyperactive Notch signaling in the osteoblast lineage.

  20. Canalis E, Parker K, Feng JQ, Zanotti S. Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology. 2013;154:623–34.

    Article  PubMed  Google Scholar 

  21. Novack DV, Teitelbaum SL. The osteoclast: friend or foe? Annu Rev Pathol. 2008;3:457–84.

    Article  PubMed  Google Scholar 

  22. • Bai S, Kopan R, Zou W, et al. NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem. 2008;283:6509–18. This study demonstrates both direct and osteoblast-mediated regulation of osteoclastogenesis by Notch.

    Article  PubMed  Google Scholar 

  23. Yamada T, Yamazaki H, Yamane T, et al. Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells. Blood. 2003;101:2227–34.

    Article  PubMed  Google Scholar 

  24. Fukushima H, Nakao A, Okamoto F, et al. The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol. 2008;28:6402–12.

    Article  PubMed  Google Scholar 

  25. Sekine C, Koyanagi A, Koyama N, Hozumi K, Chiba S, Yagita H. Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes. Arthritis Res Ther. 2012;14:R45.

    Article  PubMed  Google Scholar 

  26. Brennan AM, Pauli RM. Hajdu-Cheney syndrome: evolution of phenotype and clinical problems. Am J Med Genet. 2001;100:292–310.

    Article  PubMed  Google Scholar 

  27. Isidor B, Lindenbaum P, Pichon O, et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet. 2011;43:306–8.

    Article  PubMed  Google Scholar 

  28. Simpson MA, Irving MD, Asilmaz E, et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet. 2011;43:303–5.

    Article  PubMed  Google Scholar 

  29. • Majewski J, Schwartzentruber JA, Caqueret A, et al. Mutations in NOTCH2 in families with Hajdu-Cheney syndrome. Hum Mutat. 2011;32:1114–7. These studies identify NOTCH2 mutations as the cause for Hajdu-Cheney Syndrome.

    Article  PubMed  Google Scholar 

  30. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269–71.

    Article  PubMed  Google Scholar 

  31. Isidor B, Le Merrer M, Exner GU, et al. Serpentine fibula-polycystic kidney syndrome caused by truncating mutations in NOTCH2. Hum Mutat. 2011;32:1239–42.

    Article  PubMed  Google Scholar 

  32. Gray MJ, Kim CA, Bertola DR, et al. Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome. Eur J Hum Genet. 2012;20:122–4.

    Article  PubMed  Google Scholar 

  33. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20:251–7.

    Article  PubMed  Google Scholar 

  34. Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997;16:235–42.

    Article  PubMed  Google Scholar 

  35. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997;16:243–51.

    Article  PubMed  Google Scholar 

  36. • McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79:169–73. These studies discovered the role of impaired Notch signaling in Alagille syndrome.

    Article  PubMed  Google Scholar 

  37. Sanderson E, Newman V, Haigh SF, Baker A, Sidhu PS. Vertebral anomalies in children with Alagille syndrome: an analysis of 50 consecutive patients. Pediatr Radiol. 2002;32:114–9.

    Article  PubMed  Google Scholar 

  38. Berrocal T, Gamo E, Navalón J, et al. Syndrome of Alagille: radiological and sonographic findings. A review of 37 cases. Eur Radiol. 1997;7:115–8.

    Article  PubMed  Google Scholar 

  39. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet. 1997;34:152–7.

    Article  PubMed  Google Scholar 

  40. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr. 1995;127:220–4.

    Article  PubMed  Google Scholar 

  41. Bales CB, Kamath BM, Munoz PS, et al. Pathologic lower extremity fractures in children with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;51:66–70.

    Article  PubMed  Google Scholar 

  42. • Kung AW, Xiao SM, Cherny S, et al. Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet. 2010;86:229–39. This study Links JAG1 polymorphism with bone mineral density in a diverse human population.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the Long lab is supported by NIH grant AR055923. J. Regan is a postdoctoral fellow supported by NIH T32 HL007873.

Disclosure

J. Regan declares no conflicts of interest. F. Long declares no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Jenna Regan & Fanxin Long

  2. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA

    Fanxin Long

Authors
  1. Jenna Regan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fanxin Long
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fanxin Long.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Regan, J., Long, F. Notch Signaling and Bone Remodeling. Curr Osteoporos Rep 11, 126–129 (2013). https://doi.org/10.1007/s11914-013-0145-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-013-0145-4

Keywords

Search

Navigation