Caspase-dependent cleavage of cadherins and catenins during osteoblast apoptosis

As transmembrane, Ca2+-dependent cell-cell adhesion molecules, cadherins pl ay a central role in tissue morphogenesis and homeostasis. Stable adhesion is dependent on interactions of the cytoplasmic domain of the cadherins wit h a group of intracellular proteins, the catenins, In the present study, we have detected the expression of (alpha-, beta-, and gamma -catenins in hum an osteoblasts, which assemble with cadherins to form two distinct complexe s containing cadherin and alpha -catenin, with either beta- or gamma -caten in, In osteoblasts undergoing apoptosis, proteolytic cleavage of N-cadherin and beta- and gamma- catenins but not alpha -catenin was associated with t he activation of caspase-3 and prevented by the caspase inhibitor Z-VAD-fmk . The pattern of cadherin/catenin cleavage detected in apoptotic osteoblast s was reproduced in vitro by recombinant caspase-3, The presence of a 90-kD a extracellular domain fragment of N-cadherin in conditioned medium from ap optotic cells indicates that additional extracellular or membrane-associate d proteases also are activated. Disruption of N-cadherin-mediated cell-cen adhesion with function-blocking antibodies induced osteoblast apoptosis, ac tivation of caspases, and cleavage of beta -catenin, These findings provide compelling evidence that N-cadherin-mediated cell-cell adhesion promotes o steoblast survival and suggest that the underlying mechanism may involve ac tivation of beta -catenin signaling.