Factors regulating the response of cells cultured from human giant cell tumors of bone to parathyroid hormone.

Exposure of cells cultured from human giant cell tumors of bone to parathyroid hormone (PTH) results in an increase in the intracellular cAMP content. When cells are preincubated with PTH for periods as short as 10 min and then reexposed to this hormone, there is a decrease in the subsequent PTH-induced cAMP response. This decrease is inversely related to the concentration of PTH present during the preincubation. To investigate the factors responsible for this decrease in hormone response, we used a synthetic substituted analog of bovine PTH, [Nle8, Nle18, Tyr34]bPTH-(3-34) amide (PTH-Inh), which had previously been shown to be a competitive inhibitor of PTH-induced cAMP response in renal and bone-derived tissues. Incubation of these cultured cells with this analog failed to increase intracellular cAMP levels. In contrast to the results obtained with native hormone, when cells were preincubated with PTH-Inh, the acute cAMP response to native PTH after the removal of PTH-Inh was not diminished. In addition, simultaneous preincubation with native PTH and PTH-Inh partially overcame desensitization to PTH. These results suggest that occupancy of the PTH receptor alone is not sufficient to cause desensitization. Rather, steps subsequent to hormone binding, including activation of adenylate cyclase, may be required for the induction of a state of desensitization to PTH.