PARATHYROID-HORMONE DOWN-REGULATES 1,25-DIHYDROXYVITAMIN-D RECEPTORS (VDR) AND VDR MESSENGER-RIBONUCLEIC-ACID INVITRO AND BLOCKS HOMOLOGOUS UP-REGULATION OF VDR INVIVO

1, 25-Dihydroxyvitamin D3[1, 25(OH)2D3) is a known up-regulator of 1, 25(OH)2D3receptor (VDR) both in vitro and in vivo. However, a 5- to 10-fold increase in plasma 1, 25(OH)2D3induced by dietary calcium deficiency does not result in up-regulation of intestinal VDR, and kidney VDR is down-regulated. Under certain physiological stresses, an increase in plasma PTH precedes increased plasma 1, 25(OH)2D3. Therefore, the present study examined the effect of PTH on VDR regulation in vitro in ROS 17/2.8 cells and in vivo in male Holtzman rats. Treatment of ROS cells with PTH (0-5 nM) resulted in a dose and time-dependent decline in VDR from 95 ± 9 to 35 ± 5 fmol/mg protein at 18 h of exposure. The ED50for PTH was 1 nM. This decline in VDR protein was attended by a 50% decline in VDR messenger RNA (mRNA). The PTHmediated down-regulation of VDR occurred without affecting the affinity of VDR for 1, 25(OH)2D3as determined by Scatchard analysis. Also, the effect of PTH on VDR regulation was specific since cell glucocorticoid receptor concentration was not affected by PTH treatment. In accompanying experiments, 1, 25(OH)2- [3H]D3treatment of ROS cells was shown to result in a 3- to 4- fold increased expression of VDR and VDR mRNA. The simultaneous addition of PTH and 1, 25(OH)2[3H]D3resulted in inhibition of the l, 25(OH)2[3H]D3-mediated up-regulation of VDR and VDR mRNA. Similarly, PTH also inhibited heterologous up-regulation of VDR and VDR mRNA induced by retinoic acid. In in vivo experiments, rats infused for 5 days with 1, 25(OH)2D3(1.5 ng/h) increased their expression of intestinal VDR, kidney VDR, and kidney 24-hydroxylase by 31, 336, and 4000%, respectively. Coinfusion of PTH (1.8 IU/h) along with 1, 25(OH)2D3completely inhibited the l, 25(OH)2D3-mediated increases in intestinal VDR and kidney 24-hydroxylase and reduced the l, 25(OH)2D3-mediated up-regulation of kidney VDR by more than half. These data suggest that PTH is a potent downregulator of VDR and that PTH and 1, 25(OH)2D3have opposing effects on the expression of certain genes. © 1990 by The Endocrine Society.