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Molecular and Cellular Biology, February 2009, p. 953-964, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.00349-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

N-Cadherin Interacts with Axin and LRP5 To Negatively Regulate Wnt/β-Catenin Signaling, Osteoblast Function, and Bone Formation{triangledown}

Eric Haÿ,1,2 Emmanuel Laplantine,1,2,{dagger} Valérie Geoffroy,1,2 Monique Frain,3,4 Thomas Kohler,5 Ralph Müller,5 and Pierre J. Marie1,2*

INSERM, U606, Paris, France,1 Université Paris 7, Paris, France,2 INSERM, U784, Paris, France,3 École Normale Supérieure, Paris, France,4 Institute for Biomechanics, ETH Zurich, Zurich, Switzerland5

Received 29 February 2008/ Returned for modification 28 April 2008/ Accepted 8 December 2008

Wnt signaling plays an important role in the regulation of bone formation and bone mass. The mechanisms that regulate canonical Wnt signaling in osteoblasts are not fully understood. We show here a novel mechanism by which the adhesion molecule N-cadherin interacts with the Wnt coreceptor LRP5 and regulates canonical Wnt/β-catenin signaling in osteoblasts. We demonstrate that N-cadherin, besides associating with β-catenin at the membrane, forms a molecular complex with axin and LRP5 involving the LRP5 cytoplasmic tail domain. N-cadherin overexpression in osteoblasts increases N-cadherin-LRP5 interaction, causing increased β-catenin degradation and altered TCF/LEF transcription in response to Wnt3a. This mechanism results in decreased osteoblast gene expression and osteogenesis in basal conditions and in response to Wnt3a. Consistent with a functional mechanism, silencing N-cadherin expression in control cells increases TCF/LEF transcription and enhances the response to Wnt3a. Using N-cadherin transgenic mice, we show that increased N-cadherin-LRP5 interaction resulting from targeted overexpression of N-cadherin in osteoblasts causes increased β-catenin ubiquitination and results in cell-autonomous defective osteoblast function, reduced bone formation, and delayed bone mass acquisition. These data indicate that a previously unrecognized N-cadherin-axin-LRP5 interaction negatively regulates Wnt/β-catenin signaling and is critical in the regulation of osteoblast function, bone formation, and bone mass.

* Corresponding author. Mailing address: INSERM U606, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris cedex 10, France. Phone: 33 1 49 95 63 89. Fax: 33 1 49 95 84 52. E-mail: pierre.marie{at}larib.inserm.fr

{triangledown} Published ahead of print on 15 December 2008.

{dagger} Present address: Institut Pasteur, Paris, France.

Molecular and Cellular Biology, February 2009, p. 953-964, Vol. 29, No. 4
0270-7306/09/$08.00+0     doi:10.1128/MCB.00349-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • McCrea, P. D., Gu, D., Balda, M. S. (2009). Junctional Music that the Nucleus Hears: Cell-Cell Contact Signaling and the Modulation of Gene Activity. Cold Spring Harb. Perspect. Biol. 1: a002923-a002923 [Abstract] [Full Text]  
  • Marie, P. J. (2009). N-Cadherin-Wnt Connections and the Control of Bone Formation. IBMS BoneKEy 6: 150-156 [Abstract] [Full Text]  


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