title: Peptide-based mediated disruption of N-cadherin-LRP5/6 interaction promotes Wnt signaling and bone formation.
abstract: 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.
authors.affiliation: Laboratory of Osteoblast Biology and Pathology, INSERM UMR-606, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Haÿ
authors.forename: Thibault
authors.initials: T
authors.lastname: Buczkowski
authors.forename: Caroline
authors.initials: C
authors.lastname: Marty
authors.forename: Sophie
authors.initials: S
authors.lastname: Da Nascimento
authors.forename: Pascal
authors.initials: P
authors.lastname: Sonnet
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Marie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000737:chemistry / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010455:Peptides; D051176:beta Catenin