Abstract
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3 dramatically decreases parathyroid hormone (PTH) gene transcription. We have now studied the effect of 1,25(OH)2D3 on the 1,25(OH)2D receptor (VDR) in the parathyroid in vivo. Rats were injected with 1,25(OH)2D3 and the parathyroid-thyroid tissue analyzed for PTHmRNA and VDRmRNA. 1,25(OH)2D3 (50 and 100 pmol ip) decreased PTHmRNA at 6 h with a maximum at 48 h (less than 4% of basal), whereas VDRmRNA was increased only after 6 h with a 1.7-fold increase at 24 h. VDRmRNA levels peaked at 25 pmol 1,25(OH)2D3 with a twofold increase. Serum calcium did not affect VDRmRNA. Parathyroid VDRmRNA ran at 2.2 and 4.4 kb, whereas duodenum VDRmRNA had a single band, all of which increased after 1,25(OH)2D3. Weanling rats on a vitamin D-deficient diet for 3 wk had a more intense 2.2-kb transcript, whereas vitamin D-replete rats had a more intense 4.4-kb band. Dispersed parathyroid-thyroid cells were separated by a flow cytometry (FACS) into a parathyroid cell peak containing PTHmRNA and a second peak with cells positive for thyro-globulin mRNA and calcitonin mRNA. VDRmRNA was concentrated in the parathyroid cell peak. In situ hybridization of parathyroid-thyroid and duodenum for VDRmRNA showed its localization to the parathyroid cells and the duodenal mucosa. Therefore, the VDRmRNA in the parathyroid-thyroid tissue represents predominantly parathyroid cell and not C-cell VDRmRNA which is also a 1,25(OH)2D3 target organ. The increased VDR gene expression in the parathyroid cell would amplify the effect of 1,25(OH)2D3 to decrease PTH gene transcription.
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- Baker A. R., McDonnell D. P., Hughes M., Crisp T. M., Mangelsdorf D. J., Haussler M. R., Pike J. W., Shine J., O'Malley B. W. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci U S A. 1988 May;85(10):3294–3298. doi: 10.1073/pnas.85.10.3294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Costa E. M., Feldman D. Homologous up-regulation of the 1,25 (OH)2 vitamin D3 receptor in rats. Biochem Biophys Res Commun. 1986 Jun 13;137(2):742–747. doi: 10.1016/0006-291x(86)91141-1. [DOI] [PubMed] [Google Scholar]
- Costa E. M., Feldman D. Measurement of 1,25-dihydroxyvitamin D3 receptor turnover by dense amino acid labeling: changes during receptor up-regulation by vitamin D metabolites. Endocrinology. 1987 Mar;120(3):1173–1178. doi: 10.1210/endo-120-3-1173. [DOI] [PubMed] [Google Scholar]
- Costa E. M., Hirst M. A., Feldman D. Regulation of 1,25-dihydroxyvitamin D3 receptors by vitamin D analogs in cultured mammalian cells. Endocrinology. 1985 Nov;117(5):2203–2210. doi: 10.1210/endo-117-5-2203. [DOI] [PubMed] [Google Scholar]
- Cote G. J., Rogers D. G., Huang E. S., Gagel R. F. The effect of 1,25-dihydroxyvitamin D3 treatment on calcitonin and calcitonin gene-related peptide mRNA levels in cultured human thyroid C-cells. Biochem Biophys Res Commun. 1987 Nov 30;149(1):239–243. doi: 10.1016/0006-291x(87)91630-5. [DOI] [PubMed] [Google Scholar]
- Demay M. B., Gerardi J. M., DeLuca H. F., Kronenberg H. M. DNA sequences in the rat osteocalcin gene that bind the 1,25-dihydroxyvitamin D3 receptor and confer responsiveness to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A. 1990 Jan;87(1):369–373. doi: 10.1073/pnas.87.1.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Favus M. J., Mangelsdorf D. J., Tembe V., Coe B. J., Haussler M. R. Evidence for in vivo upregulation of the intestinal vitamin D receptor during dietary calcium restriction in the rat. J Clin Invest. 1988 Jul;82(1):218–224. doi: 10.1172/JCI113574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freake H. C., MacIntyre I. Specific binding of 1,25-dihydroxycholecalciferol in human medullary thyroid carcinoma. Biochem J. 1982 Jul 15;206(1):181–184. doi: 10.1042/bj2060181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haussler M. R., Mangelsdorf D. J., Komm B. S., Terpening C. M., Yamaoka K., Allegretto E. A., Baker A. R., Shine J., McDonnell D. P., Hughes M. Molecular biology of the vitamin D hormone. Recent Prog Horm Res. 1988;44:263–305. doi: 10.1016/b978-0-12-571144-9.50013-2. [DOI] [PubMed] [Google Scholar]
- Huang Y. C., Lee S., Stolz R., Gabrielides C., Pansini-Porta A., Bruns M. E., Bruns D. E., Miffin T. E., Pike J. W., Christakos S. Effect of hormones and development on the expression of the rat 1,25-dihydroxyvitamin D3 receptor gene. Comparison with calbindin gene expression. J Biol Chem. 1989 Oct 15;264(29):17454–17461. [PubMed] [Google Scholar]
- Hughes M. R., Malloy P. J., Kieback D. G., Kesterson R. A., Pike J. W., Feldman D., O'Malley B. W. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science. 1988 Dec 23;242(4886):1702–1705. doi: 10.1126/science.2849209. [DOI] [PubMed] [Google Scholar]
- Kerner S. A., Scott R. A., Pike J. W. Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4455–4459. doi: 10.1073/pnas.86.12.4455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Keshet E., Polakiewicz R. D., Itin A., Ornoy A., Rosen H. Proenkephalin A is expressed in mesodermal lineages during organogenesis. EMBO J. 1989 Oct;8(10):2917–2923. doi: 10.1002/j.1460-2075.1989.tb08441.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krieg P. A., Melton D. A. In vitro RNA synthesis with SP6 RNA polymerase. Methods Enzymol. 1987;155:397–415. doi: 10.1016/0076-6879(87)55027-3. [DOI] [PubMed] [Google Scholar]
- Lee Y., Inaba M., DeLuca H. F., Mellon W. S. Immunological identification of 1,25-dihydroxyvitamin D3 receptors in human promyelocytic leukemic cells (HL-60) during homologous regulation. J Biol Chem. 1989 Aug 15;264(23):13701–13705. [PubMed] [Google Scholar]
- Mahonen A., Pirskanen A., Keinänen R., Mäenpä P. H. Effect of 1,25(OH)2D3 on its receptor mRNA levels and osteocalcin synthesis in human osteosarcoma cells. Biochim Biophys Acta. 1990 Jan 30;1048(1):30–37. doi: 10.1016/0167-4781(90)90018-w. [DOI] [PubMed] [Google Scholar]
- Markose E. R., Stein J. L., Stein G. S., Lian J. B. Vitamin D-mediated modifications in protein-DNA interactions at two promoter elements of the osteocalcin gene. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1701–1705. doi: 10.1073/pnas.87.5.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McDonnell D. P., Mangelsdorf D. J., Pike J. W., Haussler M. R., O'Malley B. W. Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. Science. 1987 Mar 6;235(4793):1214–1217. doi: 10.1126/science.3029866. [DOI] [PubMed] [Google Scholar]
- Minghetti P. P., Norman A. W. 1,25(OH)2-vitamin D3 receptors: gene regulation and genetic circuitry. FASEB J. 1988 Dec;2(15):3043–3053. doi: 10.1096/fasebj.2.15.2847948. [DOI] [PubMed] [Google Scholar]
- Naveh-Many T., Friedlaender M. M., Mayer H., Silver J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat. Dominant role of 1,25-dihydroxyvitamin D. Endocrinology. 1989 Jul;125(1):275–280. doi: 10.1210/endo-125-1-275. [DOI] [PubMed] [Google Scholar]
- Naveh-Many T., Silver J. Regulation of calcitonin gene transcription by vitamin D metabolites in vivo in the rat. J Clin Invest. 1988 Jan;81(1):270–273. doi: 10.1172/JCI113305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Naveh-Many T., Silver J. Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat. J Clin Invest. 1990 Oct;86(4):1313–1319. doi: 10.1172/JCI114840. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Okazaki T., Igarashi T., Kronenberg H. M. 5'-flanking region of the parathyroid hormone gene mediates negative regulation by 1,25-(OH)2 vitamin D3. J Biol Chem. 1988 Feb 15;263(5):2203–2208. [PubMed] [Google Scholar]
- Ritchie H. H., Hughes M. R., Thompson E. T., Malloy P. J., Hochberg Z., Feldman D., Pike J. W., O'Malley B. W. An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D3-resistant rickets in three families. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9783–9787. doi: 10.1073/pnas.86.24.9783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shvil Y., Naveh-Many T., Barach P., Silver J. Regulation of parathyroid cell gene expression in experimental uremia. J Am Soc Nephrol. 1990 Jul;1(1):99–104. [PubMed] [Google Scholar]
- Silver J., Naveh-Many T., Mayer H., Schmelzer H. J., Popovtzer M. M. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest. 1986 Nov;78(5):1296–1301. doi: 10.1172/JCI112714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Silver J., Russell J., Sherwood L. M. Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4270–4273. doi: 10.1073/pnas.82.12.4270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Strom M., Sandgren M. E., Brown T. A., DeLuca H. F. 1,25-Dihydroxyvitamin D3 up-regulates the 1,25-dihydroxyvitamin D3 receptor in vivo. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9770–9773. doi: 10.1073/pnas.86.24.9770. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamamoto K. R. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet. 1985;19:209–252. doi: 10.1146/annurev.ge.19.120185.001233. [DOI] [PubMed] [Google Scholar]