Caspase-dependent cleavage of cadherins and catenins during osteoblast apoptosis

As transmembrane, Ca2+-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 (alpha-, beta-, and gamma -catenins in human osteoblasts, which assemble with cadherins to form two distinct complexes containing cadherin and alpha -catenin, with either beta- or gamma -catenin, In osteoblasts undergoing apoptosis, proteolytic cleavage of N-cadherin and beta- and gamma- catenins but not alpha -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-cen adhesion with function-blocking antibodies induced osteoblast apoptosis, activation of caspases, and cleavage of beta -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 beta -catenin signaling.