Caspase‐Dependent Cleavage of Cadherins and Catenins During Osteoblast Apoptosis

As transmembrane, Ca 2+ ‐dependent cell‐cell adhesion molecules, cadherins play a central role in tissue morphogenesis and homeostasis. Stable adhesion is dependent on interactions of the cytoplasmic domain of the cadherins with a group of intracellular proteins, the catenins. In the present study, we have detected the expression of α‐, β‐, and γ‐catenins in human osteoblasts, which assemble with cadherins to form two distinct complexes containing cadherin and α‐catenin, with either β‐ or γ‐catenin. In osteoblasts undergoing apoptosis, proteolytic cleavage of N‐cadherin and β‐ and γ‐ catenins but not α‐catenin was associated with the activation of caspase‐3 and prevented by the caspase inhibitor Z‐VAD‐fmk. The pattern of cadherin/catenin cleavage detected in apoptotic osteoblasts was reproduced in vitro by recombinant caspase‐3. The presence of a 90‐kDa extracellular domain fragment of N‐cadherin in conditioned medium from apoptotic cells indicates that additional extracellular or membrane‐associated proteases also are activated. Disruption of N‐cadherin‐mediated cell‐cell adhesion with function‐blocking antibodies induced osteoblast apoptosis, activation of caspases, and cleavage of β‐catenin. These findings provide compelling evidence that N‐cadherin‐mediated cell‐cell adhesion promotes osteoblast survival and suggest that the underlying mechanism may involve activation of β‐catenin signaling.