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

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. © 2012 American Society for Bone and Mineral Research.