STEROID REGULATION OF PARATHYROID HORMONE-RELATED PROTEIN EXPRESSION AND ACTION IN THE RAT UTERUS

The gene encoding parathyroid hormone-related protein (PTHrP), an auto crine/paracrine inhibitor of vascular and nonvascular smooth muscle co ntractility, is regulated by hormonal steroids including estrogens (E( 2)), 1,25-dihydroxy vitamin D (Vit D-3) and glucocorticoids. While E(2 ) increases PTHrP gene expression, Vit D-3 and glucocorticoids inhibit transcriptional activity of this gene. In the uterus of ovariectomize d rats, E(2)-treatment increases both PTHrP mRNA levels and smooth mus cle sensitivity to the action of PTHrP(1-34). To examine the action(s) of Vit D-3 and glucocorticoids on these parameters, OVX rats were tre ated with E(2), Vit D-3 or the synthetic glucocorticoid, dexamethasone (Dex), alone, or with E(2) following a 1 h pretreatment with Vit D-3 or Dex. PTHrP and PTH/PTHrP receptor mRNA were measured by blot hybrid ization analysis of RNA prepared from uteri collected 2, 4 and 24 h af ter treatment. Uterine horns were used to measure the effect of the st eroids on the ability of PTHrP(1-34) to inhibit spontaneous myometrial contraction. When E(2), Vit D-3 and Dex were given alone, only E(2) a ltered PTHrP mRNA levels in the uterus, however, a 1 h pretreatment wi th Dex but not Vit D-3 markedly diminished this effect of E(2). The te mporal decline in uterine PTH/PTHrP receptor mRNA levels measured 2 an d 4 h after E(2) treatment inversely correlated to changes in sensitiv ity of the tissue to PTHrP(1-34) measured at 24 h after E(2) administr ation. In comparison to E(2) alone, treatment with Vit D-3 and E(2) au gmented the uterine responsiveness to PTHrP(1-34) while pretreatment w ith Dex (1 mg/kg) and E(2) decreased this response. These data indicat e that in the uterus, Dex opposes the positive effect of E(2) on PTHrP gene activity and differentially modulates the action of PTHrP on myo metrial tone. Moreover, elevations in the circulating levels of cortis ol at term may serve to decrease both the uterine expression of PTHrP and the local action of PTHrP on the myometrium prior to parturition, therefore promoting myometrial contraction associated with labor.