COORDINATE REGULATION OF PTH PTHRP RECEPTORS BY PTH AND CALCITRIOL INUMR-106-01 OSTEOBLAST-LIKE CELLS/

High levels of PTH result in desensitization of target cells to furthe r stimulation with PTH in vivo and in vitro. While studies in vitro de monstrate that the effect of PTH can be direct, it is also possible th at 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 P TH/THrP-receptor expression in confluent cultures of UMR 106-01 osteob last-like cells treated with calcitriol, PTH or both hormones for one to three days. Following these treatments, studies of PTH receptor bin ding, cAMP generation, and steady-state levels of PTH/PTHrP receptor m RNA were performed. Exposure to PTH resulted in a decrease in PTH stim ulated cAMP generation by 88 +/- 2%, and PTH binding by 63 +/- 3%. Lev els of PTH/PHrP-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-recep tor mRNA, decreasing by 72 +/- 4% after 38 hours. PTH receptor binding and cAMP generation were diminished by 42 +/- 3% and 42 +/- 4%, respe ctively. Co-incubation of UMR 106-01 cells with submaximal doses of ca lcitriol and PTH together revealed that the levels of PTH/PTHrP-recept or mRNA were decreased by both hormones together to a greater extent t han with either alone. These studies show that both calciotropic hormo nes, PTH and calcitriol, are potent regulators of PTH/THrP-receptor ge ne expression in UMR 106-01 osteoblast-like cells. Thus, stimulation o f calcitriol production by PTH may result in a coordinated down-regula tion of PTH receptor expression by these hormones.