Peptide-based mediated disruption of N-cadherin-LRP5/6 interaction promotes Wnt signaling and bone formation

J Bone Miner Res. 2012 Sep;27(9):1852-63. doi: 10.1002/jbmr.1656.


Wnt signaling plays an important role in skeletal biology and diseases. In osteoblasts, we recently showed that the cell-cell adhesion molecule N-cadherin interacts with the Wnt coreceptors LRP5/6 to regulate osteogenesis. In this study we investigated whether targeting the intracellular domain of N-cadherin that interacts with LRP5/6 may promote Wnt signaling and bone formation. By investigating the molecular interactions between the Wnt coreceptors LRP5/6 and N-cadherin, we identified specific LRP5/6- and N-cadherin-interacting intracellular domains that impact Wnt/β-catenin signaling in murine osteoblasts. We showed that truncated N-cadherin constructs that impair N-cadherin-LRP5/6 interactions promote Wnt/β-catenin signaling and osteoblast differentiation. Based on this finding, we developed a peptide-based approach targeting N-cadherin-LRP5 interaction for promoting Wnt signaling and osteoblast function. We found that a competitor peptide containing the 28 last amino acids of LRP5 disrupts LRP5/6-N-cadherin interaction and thereby enhances Wnt/β-catenin signaling in osteoblasts. We also show that the peptide-mediated disruption of N-cadherin-LRP5/6 interaction increases Wnt/β-catenin signaling and osteoblast function in vitro and promotes calvaria bone formation in vivo. The targeted competitor peptide-based strategy reported here may provide a novel approach to stimulate Wnt/β-catenin signaling that can be used for promoting osteoblast function and bone formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cadherins / chemistry
  • Cadherins / metabolism*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Female
  • Low Density Lipoprotein Receptor-Related Protein-5 / chemistry
  • Low Density Lipoprotein Receptor-Related Protein-5 / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-6 / chemistry
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
  • Mice
  • Molecular Sequence Data
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteogenesis / drug effects*
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Binding / drug effects
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Wnt Signaling Pathway / drug effects*
  • beta Catenin / metabolism


  • Cadherins
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Peptides
  • beta Catenin