Cadherins and Wnt signalling: a functional link controlling bone formation.

Cadherins are calcium-dependent cell adhesion molecules that have a major role in morphogenesis and tissue formation. In bone, cadherins control osteoblast differentiation by mediating cell-cell adhesion and signals that promote phenotypic osteoblast gene expression. Furthermore, cadherins can interact with Wnt signalling to modulate osteoblastogenesis. One mechanism involves the interaction of N-cadherin with β-catenin at the cell membrane, resulting in β-catenin sequestration, reduction of the cytosolic β-catenin pool and inhibition of Wnt signalling. In addition to modulating the β-catenin pool, N-cadherin can regulate osteoblasts by interacting with the Wnt coreceptors LRP5 or LRP6. We showed that the functional interaction between N-cadherin and LRP5/6 in osteoblasts promotes β-catenin degradation and reduces canonical Wnt signalling. This crosstalk between N-cadherin and Wnt signalling has a negative impact on osteoblast proliferation, differentiation and survival, independently of cell-cell adhesion, which results in decreased bone formation and delayed bone accrual in mice. The identification of this crosstalk between N-cadherin and Wnt signalling may have therapeutic implications, as a disruption of the N-cadherin-LRP5/6 interaction using a competitor peptide can increase Wnt/β-catenin signalling without affecting cell-cell adhesion, and this effect results in increased osteoblastogenesis and bone tissue formation in vivo. In this review, we summarize our current knowledge of the key crosstalks between cadherins and Wnt signalling that impact osteoblast function, bone formation and bone mass, and the possible therapeutic implications of such interactions for promoting osteoblastogenesis, bone formation and bone mass.