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

The gene encoding parathyroid hormone-related protein (PTHrP), an autocrine/paracrine inhibitor of vascular and nonvascular smooth muscle contractility, 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 ovariectomized rats, E(2)-treatment increases both PTHrP mRNA levels and smooth muscle 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 treated 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 hybridization analysis of RNA prepared from uteri collected 2, 4 and 24 h after treatment. Uterine horns were used to measure the effect of the steroids 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) altered PTHrP mRNA levels in the uterus, however, a 1 h pretreatment with Dex but not Vit D-3 markedly diminished this effect of E(2). The temporal decline in uterine PTH/PTHrP receptor mRNA levels measured 2 and 4 h after E(2) treatment inversely correlated to changes in sensitivity of the tissue to PTHrP(1-34) measured at 24 h after E(2) administration. In comparison to E(2) alone, treatment with Vit D-3 and E(2) augmented the uterine responsiveness to PTHrP(1-34) while pretreatment with Dex (1 mg/kg) and E(2) decreased this response. These data indicate that in the uterus, Dex opposes the positive effect of E(2) on PTHrP gene activity and differentially modulates the action of PTHrP on myometrial tone. Moreover, elevations in the circulating levels of cortisol 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.