Schnurri-3: A Key Regulator of Postnatal Skeletal Remodeling

  • Dallas C. Jones
  • Marc N. Wein
  • Laurie H. Glimcher
Part of the Advances in Experimental Medicine and Biology book series (volume 602)

Schnurri-3, a large zinc finger protein distantly related to Drosophila Shn, is a potent and essential regulator of adult bone formation. Mice lacking Shn3 display an osteosclerotic phenotype with profoundly increased bone mass due to augmented osteoblast activity. Shn3 controls protein levels of Runx2, the principal regulator of osteoblast differentiation, by promoting its degradation. In osteoblasts, Shn3 functions as a component of a trimeric complex between Runx2 and the E3 ubiquitin ligase WWP1. This complex inhibits Runx2 function and expression of genes involved in extracellular matrix mineralization due to the ability of WWP1 to promote Runx2 polyubiquitination and proteasome-dependent degradation. Our study reveals an essential role for Shn3 as a regulator of postnatal bone mass. Compounds designed to block Shn3/WWP1 function may be possible therapeutic agents for the treatment of osteoporosis.


293T Cell Osteoblast Differentiation Increase Bone Mass Runx2 Protein Cleidocranial Dysplasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Affolter, M., T. Marty, M.A. Vigano, and A. Jazwinska. 2001. Nuclear interpretation of Dpp signaling in Drosophila. Embo J 20(13): 3298–3305.CrossRefPubMedGoogle Scholar
  2. Ducy, P., M. Starbuck, M. Priemel, J. Shen, G. Pinero, V. Geoffroy, M. Amling, and G. Karsenty. 1999. A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev 13(8): 1025–1036.CrossRefPubMedGoogle Scholar
  3. Ingham, R.J., G. Gish, and T. Pawson. 2004. The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture. Oncogene 23(11): 1972–1984.CrossRefPubMedGoogle Scholar
  4. Jones, D.C., M.N. Wein, M. Oukka, J.G. Hofstaetter, M.J. Glimcher, and L.H. Glimcher. 2006. Regulation of adult bone mass by the zinc finger adapter protein Schnurri-3. Science 312(5777): 1223–1227.CrossRefPubMedGoogle Scholar
  5. Karsenty, G., and E.F. Wagner. 2002. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2(4): 389–406.CrossRefPubMedGoogle Scholar
  6. Komori, T., H. Yagi, S. Nomura, A. Yamaguchi, K. Sasaki, K. Deguchi, Y. Shimizu, R.T. Bronson, Y.H. Gao, M. Inada, M. Sato, R. Okamoto, Y. Kitamura, S. Yoshiki, and T. Kishimoto. 1997. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89(5): 755–764.CrossRefPubMedGoogle Scholar
  7. Lee, B., K. Thirunavukkarasu, L. Zhou, L. Pastore, A. Baldini, J. Hecht, V. Geoffroy, P. Ducy, and G. Karsenty. 1997. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet 16(3): 307–310.CrossRefPubMedGoogle Scholar
  8. Li, J., I. Sarosi, X.Q. Yan, S. Morony, C. Capparelli, H.L. Tan, S. McCabe, R. Elliott, S. Scully, G. Van, S. Kaufman, S.C. Juan, Y. Sun, J. Tarpley, L. Martin, K. Christensen, J. McCabe, P. Kostenuik, H. Hsu, F. Fletcher, C.R. Dunstan, D.L. Lacey, and W.J. Boyle. 2000. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97(4): 1566–1571.CrossRefPubMedGoogle Scholar
  9. Mundlos, S., F. Otto, C. Mundlos, J.B. Mulliken, A.S. Aylsworth, S. Albright, D. Lindhout, W.G. Cole, W. Henn, J.H. Knoll, M.J. Owen, R. Mertelsmann, B.U. Zabel, and B.R. Olsen. 1997. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89(5): 773–779.CrossRefPubMedGoogle Scholar
  10. Nakashima, K., X. Zhou, G. Kunkel, Z. Zhang, J.M. Deng, R.R. Behringer, and B. de Crombrugghe. 2002. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108(1): 17–29.CrossRefPubMedGoogle Scholar
  11. Otto, F., A.P. Thornell, T. Crompton, A. Denzel, K.C. Gilmour, I.R. Rosewell, G.W. Stamp, R.S. Beddington, S. Mundlos, B.R. Olsen, P.B. Selby, and M.J. Owen. 1997. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89(5): 765–771.CrossRefPubMedGoogle Scholar
  12. Oukka, M., S.T. Kim, G. Lugo, J. Sun, L.C. Wu, and L.H. Glimcher. 2002. A mammalian homolog of Drosophila schnurri, KRC, regulates TNF receptor-driven responses and interacts with TRAF2. Mol Cell 9(1): 121–131.CrossRefPubMedGoogle Scholar
  13. Oukka, M., M.N. Wein, and L.H. Glimcher. 2004. Schnurri-3 (KRC) interacts with c-Jun to regulate the IL-2 gene in T cells. J Exp Med 199(1): 15–24.CrossRefPubMedGoogle Scholar
  14. Patterson, C. 2002. A new gun in town: the U box is a ubiquitin ligase domain. Sci STKE 2002(116): PE4.CrossRefPubMedGoogle Scholar
  15. Pickart, C.M. 2004. Back to the future with ubiquitin. Cell 116(2): 181–190.CrossRefPubMedGoogle Scholar
  16. Stein, G.S., J.B. Lian, A.J. van Wijnen, J.L. Stein, M. Montecino, A. Javed, S.K. Zaidi, D.W. Young, J.Y. Choi, and S.M. Pockwinse. 2004. Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene 23(24): 4315–4329.CrossRefPubMedGoogle Scholar
  17. Whyte, M.P. 2003. Sclerosing Bone Disorders. Primer on the metabolic Bone Diseases and Disorders of mineral metabolism (5th ed). The American Society for Bone and Mineral Research; 449–465.Google Scholar
  18. Wu, L.C., C.H. Mak, N. Dear, T. Boehm, L. Foroni, and T.H. Rabbitts. 1993. Molecular cloning of a zinc finger protein which binds to the heptamer of the signal sequence for V(D) J recombination. Nucleic Acids Res 21(22): 5067–5073.CrossRefPubMedGoogle Scholar
  19. Yamashita, M., S.X. Ying, G.M. Zhang, C. Li, S.Y. Cheng, C.X. Deng, and Y.E. Zhang. 2005. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell 121(1): 101–113.CrossRefPubMedGoogle Scholar
  20. Yang, X., K. Matsuda, P. Bialek, S. Jacquot, H.C. Masuoka, T. Schinke, L. Li, S. Brancorsini, P. Sassone-Corsi, T.M. Townes, A. Hanauer, and G. Karsenty. 2004. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell 117(3): 387–398.CrossRefPubMedGoogle Scholar
  21. Zamurovic, N., D. Cappellen, D. Rohner, and M. Susa. 2004. Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. J Biol Chem 279(36): 37704–37715.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Dallas C. Jones
    • 1
  • Marc N. Wein
    • 1
  • Laurie H. Glimcher
    • 1
  1. 1.Department of Infectious Disease and ImmunologyHarvard School of Public HealthBostonUSA

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