Parathyroid hormone (PTH) is one of the most potent stimulators of growth plate chondrocyte mitogenesis that has been reported. However, study of the second messenger signaling mechanisms involved in the transduction of the hormone's effects on these cells is incomplete. Our data indicate that in addition to stimulating cyclic adenosine-3'5'-monophosphate metabolism, PTH also activates the phosphoinositide cascade, the pathway responsible for the generation of inositol-1,4,5-trisphosphate dependent Ca2+ signals. Our conclusion that PTH activates the phosphoinositide cascade is based on data that demonstrate: (1) the Ca2+ transients evoked by the hormone are dependent on intracellular Ca2+ stores; (2) the hormone stimulates the release of radiolabeled inositol from GPC plasma membranes; and (3) the hormone stimulates a greater than 8-fold increase in cytosolic inositol-1,4,5-trisphosphate pool size.