Coordinate regulation of PTH/PTHrP receptors by PTH and calcitriol in UMR 106-01 osteoblast-like cells.

High levels of PTH result in desensitization of target cells to further stimulation with PTH in vivo and in vitro. While studies in vitro demonstrate that the effect of PTH can be direct, it is also possible that studies in vivo may be complicated by the fact that other potential regulators of PTH action, such as increased levels of calcitriol, may play a role. Thus, we examined the actions of calcitriol and PTH on PTH/PTHrP-receptor expression in confluent cultures of UMR 106-01 osteoblast-like cells treated with calcitriol, PTH or both hormones for one to three days. Following these treatments, studies of PTH receptor binding, cAMP generation, and steady-state levels of PTH/PTHrP receptor mRNA were performed. Exposure to PTH resulted in a decrease in PTH stimulated cAMP generation by 88 +/- 2%, and PTH binding by 63 +/- 3%. Levels of PTH/PTHrP-receptor mRNA decreased progressively reaching 20% of control values after three days of PTH (100 nM) treatment. Calcitriol also resulted in a dose and time-dependent decrease in PTH/PTHrP-receptor mRNA, decreasing by 72 +/- 4% after 48 hours. PTH receptor binding and cAMP generation were diminished by 42 +/- 3% and 42 +/- 4%, respectively. Co-incubation of UMR 106-01 cells with submaximal doses of calcitriol and PTH together revealed that the levels of PTH/PTHrP-receptor mRNA were decreased by both hormones together to a greater extent than with either alone. These studies show that both calciotropic hormones, PTH and calcitriol, are potent regulators of PTH/PTHrP-receptor gene expression in UMR 106-01 osteoblast-like cells. Thus, stimulation of calcitriol production by PTH may result in a coordinated down-regulation of PTH receptor expression by these hormones.