1. N-Cadherin Interacts with Axin and LRP5 To Negatively Regulate Wnt/β-Catenin Signaling, Osteoblast Function, and Bone Formation
- Author
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Valerie Geoffroy, Pierre J. Marie, Thomas Kohler, Ralph Müller, Eric Hay, Emmanuel Laplantine, Monique Frain, Os et articulations, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique moléculaire du développement, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-IFR36-Institut National de la Santé et de la Recherche Médicale (INSERM), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institute for Biomechanics, and Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)
- Subjects
MESH: Signal Transduction ,MESH: Organ Size ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Cellular differentiation ,MESH: beta Catenin ,MESH: Animals, Newborn ,MESH: Cadherins ,MESH: Down-Regulation ,Mice ,0302 clinical medicine ,MESH: Wnt3 Protein ,Osteogenesis ,MESH: Axin Protein ,MESH: Animals ,MESH: Osteogenesis ,beta Catenin ,0303 health sciences ,[SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior ,Wnt signaling pathway ,[SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences ,Cell Differentiation ,Osteoblast ,LRP5 ,Organ Size ,Articles ,MESH: Bone and Bones ,Cadherins ,Cell biology ,MESH: Wnt Proteins ,Low Density Lipoprotein Receptor-Related Protein-5 ,medicine.anatomical_structure ,MESH: Repressor Proteins ,030220 oncology & carcinogenesis ,Protein Binding ,Signal Transduction ,MESH: Cell Differentiation ,Beta-catenin ,MESH: Rats ,MESH: Mice, Transgenic ,Down-Regulation ,Mice, Transgenic ,Biology ,Bone and Bones ,Cell Line ,Wnt3 Protein ,MESH: LDL-Receptor Related Proteins ,03 medical and health sciences ,Axin Protein ,Wnt3A Protein ,medicine ,Animals ,Humans ,MESH: Protein Binding ,MESH: Wnt3A Protein ,MESH: Mice ,Molecular Biology ,LDL-Receptor Related Proteins ,030304 developmental biology ,MESH: Osteoblasts ,Osteoblasts ,MESH: Humans ,Ubiquitination ,Cell Biology ,MESH: Low Density Lipoprotein Receptor-Related Protein-5 ,Molecular biology ,Rats ,MESH: Cell Line ,Repressor Proteins ,Wnt Proteins ,Animals, Newborn ,biology.protein ,MESH: Ubiquitination ,WNT3A - Abstract
International audience; 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/beta-catenin signaling in osteoblasts. We demonstrate that N-cadherin, besides associating with beta-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 beta-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 beta-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/beta-catenin signaling and is critical in the regulation of osteoblast function, bone formation, and bone mass.
- Published
- 2009