In order to define a physiological function for cell-to-cell communication in ensembles of bone cells, we examined hormonal responsiveness in uncoupled transfectants that maintained phenotypic characteristics typical of osteoblastic cells. PTH was chosen because it is a potent regulator of bone metabolism exerting a direct effect on osteoblastic behavior (42). In osteoblastic cells such as ROS, PTH, via binding to its receptor, activates multiple second messenger systems, including the cAMP-protein kinase A cascade (43). Indeed, we found that PTH stimulated cAMP accumulation in a concentrationdependent manner in ROS, as has been previously demonstrated (39,41). However, in antisense transfectants RCx4 and RCx16, cells exhibiting decreased Cx43 and, consequently, decreased coupling, PTH-stimulated cAMP accumulation was dramatically attenuated. Additionally, we found that subconfluent ROS and bG, cells that display decreased coupling, similarly demonstrated decreased cAMP responses to PTH. However, the cAMP response to PTH was greater in subconfluent ROS and bG than in antisense transfectants, probably because coupling was greater in subconfluent ROS and bG relative to antisense transfectants. Taken together, these **data** indicate that a decrease in cell-to-cell coupling contributes to decreased hormonal responsiveness in ROS.