Skip to main content

Advertisement

SpringerLink
Log in

Recent advances in the molecular mechanism of action of 1, 25-dihydroxyvitamin D3

  • 3. Calcium, Vitamin D And Osteoporosis
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

The historical basis of recent investigations on the molecular mechanism of action of vitamin D is discussed. A summary of the recent findings in regard to the 1,25-(OH)2D3 receptor has been presented, including the structural deductions, photoaffinity labeling, sites of monoclonal antibody interaction, and sites of phosphorylation. New information on the regulation of the 1, 25-(OH)2D3 receptor have been provided together with possible reasons for this regulation. Finally, analogs of 1, 25-(OH)2D3 have been describe which carry out some of the functions of 1, 25-(OH)2D3 but not others. These analogs appear to induce transcription both in vivo andin vitro of certain genes but are not able to support calcium mobilization. Their use in therapy has been suggested as has been their use in helping unravel the molecular mechanism of action of vitamin D.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. DeLuca, H. F.: The vitamin D story: A collaborative effort of basic science and clinical medicine. FASEB J. 2, 224–236, 1988.

    CAS  PubMed  Google Scholar 

  2. DeLuca, H. F.: The vitamin D story: A success of basic science in the treatment of disease. In: Metabolic Bone Diseases in Children (S. Castells and Finberg, L., eds.), Marcell Dekker, New York, pp. 1–41, 1990.

    Google Scholar 

  3. Pike, J. W.: Emerging concepts on the biologic role and mechanism of action of 1, 25-dihydroxyvitamin D3. Steroids 49, 3–27, 1987.

    Article  CAS  PubMed  Google Scholar 

  4. Hayashi, S., Noshiro, M. and Okuda, K.: Isolation of a cytochrome P-450 that catalyzes the 25-hydroxylation of vitamin D3 from rat liver microsomes. J. Biochem. (Tokyo) 99, 1753–1756, 1986.

    CAS  Google Scholar 

  5. Usui, E., Noshiro, M. and Okuda, K.: Molecular cloning of cDNA for vitamin D3 25-hydroxylase from rat liver mitochondria. FEBS Lett. 262, 135–138, 1990.

    Article  CAS  PubMed  Google Scholar 

  6. Burt, R. E. and Crivello, J. F.: Characterization of monoclonal antibodies specific to bovine renal vitamin D hydroxylases. Endocrinology 123, 2491–2499, 1988.

    Google Scholar 

  7. Horiuchi, N., Suda, T., Takahashi, H., Shimazawa, E. and Ogata, E.: In vivo evidence for the intermediary role of 3', 5'-cyclic AMP in parathyroid hormone-induced stimulation of 1α, 25-dihydroxyvitamin D3 synthesis in rats. Endocrinology 101, 969–974, 1977.

    CAS  PubMed  Google Scholar 

  8. Barbour, G. L., Coburn, J. W., Slatopolsky, E., Norman, A. W. and Horst, R. L.: Hypercalcemia in an anephric patient with sarcoidosis: Evidence for extrarenal generation of 1, 25-dihydroxyvitamin D. New Engl. J. Med. 305, 440–443, 1981.

    CAS  PubMed  Google Scholar 

  9. Fetchick, D. A., Bertolini, D. R., Sarin, P. S., Weintraub, S. T., Mundy, G.R. and Dunn, J. F.: Production of 1, 25-dihydroxyvitamin D3 by human T-cell lymphotrophic virus-I-transformed lymphocytes. J. Clin. Invest. 78, 592–595, 1986.

    CAS  PubMed  Google Scholar 

  10. DeLuca, H. F. and Schnoes, H. K.: Vitamin D: Metabolism and mechanism of action. In: Annual Reports in Medicinal Chemistry (D. M. Bailey, ed.), Academic Press, New York. Vol. 19, Chapter 18, pp. 179–190, 1984.

    Google Scholar 

  11. Brommage, R. and DeLuca, H. F.: Evidence that 1, 25-dihydroxyvitamin D3 is the physiologically active metabolite of vitamin D3. Endocrine Rev. 6, 491–511, 1985.

    CAS  Google Scholar 

  12. Hodsman, A. B., Wong, E. G. C., Sherrard, D. J., Brickman, A. S., Lee, D. B.N., Singer, F. R., Norman, A. W. and Coburn, J. W.: Preliminary trials with 24, 25-dihydroxyvitamin D3 in dialysis osteomalacia. Amer. J. Med. 74, 407–409, 1983.

    CAS  PubMed  Google Scholar 

  13. Link, R. and DeLuca, H. F.: The vitamin D receptor. In: The Receptors (P. M. Conn, ed.), Academicd Press, New York. Vol. II, pp. 1–35, 1985.

    Google Scholar 

  14. Barsony, J., Pike, J. W., DeLuca, H. F. and Marx, S. J.: Immunocytology with microwave-fixed fibroblasts shows 1α, 25-dihydroxycholecalciferol dependent rapid and estrogen dependent slow reorganization of vitamin D receptors. J. Cell. Biol., in press, 1990.

  15. Nemere, I., Yoshimoto, Y. and Norman, A. W.: Calcium transport in perfused duodena from normal chicks: Enhancement within fourteen minutes of exposure to 1, 25-dihydroxyvitamin D3 Endocrinology 115, 1476–1483, 1984.

    CAS  PubMed  Google Scholar 

  16. Rasmussen, H., Matsumoto, T., Fontaine, O. and Goodman, D. B. P.: Role of changes in membrane lipid structure in the action of 1, 25-dihydroxyvitamin D3 Fed. Proc. 41, 72–77, 1982.

    CAS  Google Scholar 

  17. Yamamoto, M., Kawanobe, Y., Takahashi, H., Shimazawa, E., Kimura, S. and Ogata, E.: Vitamin D deficiency and renal calcium transport in the rat. J. Clin. Invest. 74, 507–513, 1984.

    CAS  PubMed  Google Scholar 

  18. Stern, P. H., Halloran, B. P., DeLuca, H. F. and Hefley, T. J.: Responsiveness of vitamin D-deficient fetal rat limb bones to parathyroid hormone in culture. Am. J. Physiol. 244, E421-E424, 1983.

    CAS  PubMed  Google Scholar 

  19. Stumpf, W. E., Sar, M. and DeLuca, H. F.: Sites of action of 1, 25 (OH) xvitamin D3 identified by thaw-mount autoradiography. In: Hormonal Control of Calcium Metabolism (D. V. Cohn, Talmage, R. V. and Matthews, J. L., eds.), Excerpta Medica, Amsterdam. pp. 222–229, 1981.

    Google Scholar 

  20. Abe, E., Ishimi, Y., Takahashi, N., Akatsu, T., Ozawa, H., Yamana, H., Yoshiki, S. and Suda, T.: A differentiation-inducing factor produced by the osteoblastic cell line MC3T3-E1 stimulates bone resorption by promoting osteoclast formation. J. Bone Min. Res. 3, 635–647, 1988.

    CAS  Google Scholar 

  21. Horton, M. A., Lewis, D., McNulty, K., Pringle, J. A. S. and Chambers, T. J.: Monoclonal antibodies to osteoclastomas (giant cell bone tumors): Definition of osteoclast-specific cellular antigens. Cancer Res. 45, 5663–5669, 1985.

    CAS  PubMed  Google Scholar 

  22. Jin, C. H., Segawa, A., Miyaura, C., Tanaka, H., Abe, E. and Suda, T.: Calcium is essential in the fusion of mouse alveolar macrophages induced by 1α, 25-dihydroxyvitamin D3. J. Cell. Physiol. 137, 110–116, 1988.

    Article  CAS  PubMed  Google Scholar 

  23. Sherwood, L. M. and Russell, J.: The role of 1, 25-(OH)2D3 in regulating parathyroid gland function. Proc. Soc. Exp. Biol. Med. 191, 233–237, 1989.

    CAS  PubMed  Google Scholar 

  24. Chertow, B. S., Sivitz, W. I., Baranetsky, N. G., Clark, S. A., Waite, A. and DeLuca, H. F.: Cellular mechanisms of insulin release. The effects of vitamin D deficiency and repletion on rat insulin secretion. Endocrinology 113, 1511–1518, 1983.

    CAS  PubMed  Google Scholar 

  25. Hosomi, J., Hosoi, J., Abe, E., Suda, T. and Kuroki, T.: Regulation of terminal differentiation of cultured mouse epidermal cells by 1α,25-dihydroxyvitamin D3. Endocrinology 113, 1950–1957, 1983.

    CAS  PubMed  Google Scholar 

  26. Holick, M. F.: 1, 25-Dihydroxyvitamin D3 and the skin: A unique application for the treatment of psoriasis. Proc. Soc. Exp. Biol. Med. 191, 246–257, 1989.

    CAS  PubMed  Google Scholar 

  27. Kwiecinski, G. G., Petrie, G. I. and DeLuca, H. F.: Vitamin D is necessary for reproductive functions of the male rat. J. Nutr. 119, 741–744, 1989.

    CAS  PubMed  Google Scholar 

  28. Kwiecinski, G. G., Petrie, G. I. and DeLuca, H. F.: 1, 25-Dihydroxyvitamin D3 restores fertility of vitamin D-deficient female rats. Am. J. Physiol. 256, E483-E487, 1989.

    Google Scholar 

  29. Brumbaugh, P. F. and Haussler, M. R.: Nuclear and cytoplasmic binding components for vitamin D metabolites. Life Sci. 16, 353–362, 1975.

    Article  CAS  PubMed  Google Scholar 

  30. Kream, B. E., Reynolds, R. D., Knutson, J. C., Eisman, J. A. and DeLuca, H. F.: Intestinal cytosol binders of 1, 25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3. Arch. Biochem. Biophys. 176, 779–787, 1976.

    Article  CAS  PubMed  Google Scholar 

  31. Simpson, R. U., Hamstra, A., Kendrick, N. C. and DeLuca, H. F.: Purification of the receptor for 1α, 25-dihydroxyvitamin D3 from chicken intestine. Biochemistry 22, 2586–2594, 1983.

    Article  CAS  PubMed  Google Scholar 

  32. Pike, J. W., Marion, S. L., Donaldson, C. A. and Haussler, M. R.: Serum and monoclonal antibodies against the chick intestinal receptor for 1, 25-dihydroxyvitamin D3. J. Biol. Chem. 258, 1289–1296, 1983.

    CAS  PubMed  Google Scholar 

  33. Dame, M. C., Pierce, E. A., Prahl, J. M., Hayes, C. E. and DeLuca, H. F.: Monoclonal antibodies to the porcine intestinal receptor for 1, 25-dihydroxyvitamin D3: Interaction with distinct receptor domains. Biochemistry 25, 4523–4534, 1986.

    Article  CAS  PubMed  Google Scholar 

  34. Dame, M. C., Pierce, E. A. and DeLuca, H. F.: Identification of the porcine intestinal 1, 25-dihydroxyvitamin D3 receptor on sodium dodecyl sulfate-polyacrylamide gels by renaturation and immunoblotting. Proc. Natl. Acad. Sci. USA 82, 7825–7829, 1985.

    CAS  PubMed  Google Scholar 

  35. Mangelsdorf, D. J., Pike, J. W. and Haussler, M. R.: Avian and mammalian receptors for 1, 25-dihydroxyvitamin D3: In vitro translation to characterizesize and hormone-dependent regulation. Proc. Natl. Acad. Sci. USA 84, 354–358, 1987.

    CAS  PubMed  Google Scholar 

  36. Pierce, E. A., Dame, M. C. and DeLuca, H. F.: Size and charge of the functional 1, 25-dihydroxyvitamin D receptor in porcine intestine. J. Biol. Chem. 262, 17092–17099, 1987.

    CAS  PubMed  Google Scholar 

  37. Burmester, J. K., Maeda, N. and DeLuca, H. F.: Isolation and expression of rat 1, 25-dihydroxyvitamin D3 receptor cDNA. Proc. Natl. Acad. Sci. USA 85, 1005–1009, 1988.

    CAS  PubMed  Google Scholar 

  38. Burmester, J. K., Wiese, R. J., Maeda, N. and DeLuca, H. F.: Structure and regulation of the rat 1, 25-dihydroxyvitamin D3 receptor. Proc. Natl. Acad.Sci. USA 85, 9499–9502, 1988.

    CAS  PubMed  Google Scholar 

  39. Baker, A. R., McDonnell, D. P., Hughes, M., Crisp, T. M., Mangelsdorf, D. J., Haussler, M. R., Pike, J. W., Shine, J. and O'Malley, B. W.: Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc. Natl. Acad. Sci. USA 85, 3294–3298, 1988.

    CAS  PubMed  Google Scholar 

  40. McDonnell, D. P., Mangelsdorf, D. J., Pike, J. W., Haussler, M. R. and O'Malley, B. W.: Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. Science 235, 1214–1217, 1987.

    CAS  PubMed  Google Scholar 

  41. McDonnell, D. P., Scott, R. A., Kerner, S. A., O'Malley, B. W. and Pike, J. W.: Functional domains of the human vitamin D3 receptor egulate osteocalcin gene expressions. Mol. Endocrinol. 3, 635–637, 1989.

    CAS  PubMed  Google Scholar 

  42. Brown, T. A. and DeLuca, H. F.: Photoaffinity labeling of the 1, 25-dihydroxyvitamin D3 receptor. Biochim. Biophys. Acta., in press, 1990.

  43. Brown, T. A., Prahl, J. M. and DeLuca, H. F.: Partial amino acid sequence of porcine 1, 25-dihydroxyvitamin D3 receptor isolated by immunoaffinity chromatography. Proc. Natl. Acad. Sci. USA 85, 2454–2458, 1988.

    CAS  PubMed  Google Scholar 

  44. Hughes, M. R., Malloy, P. J., Kieback, D. G., Kesterson, R. A., Pike, J. W., Feldman, D. and O'Malley, B. W.: Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science 242, 1702–1706, 1988.

    CAS  PubMed  Google Scholar 

  45. Sone, T., Scott, R. A., Hughes, M. R., Malloy, P. J., Feldman, D., O'Malley, B. W. and Pike, J. W.: Mutant vitamin D receptors which confer hereditary resistance to 1, 25-dihydroxyvitamin D3 in humans are transcriptionally inactivein vitro. J. Biol. Chem. 264, 20230–20234, 1989.

    CAS  PubMed  Google Scholar 

  46. Sone, T., McDonnell, D. P., O'Malley, B. W. and Pike, J. W.: Expression and large scale purification of recombinant human vitamin D receptor from s. cerevisiae. J. Bone Min. Res., no. 537, S208 (abstract), 1990.

  47. Brown, T. A. and DeLuca, H. F.: Phosphorylation of the 1, 25-dihydroxyvitamin D3 receptor: A primary event in 1, 25-dihydroxyvitamin D3 action. J. Biol. Chem. 265, 10025–10029, 1990.

    CAS  PubMed  Google Scholar 

  48. Pike, J. W. and Sleator, N. M.: Hormone-dependent phosphorylation of the 1,25-dihydroxyvitamin D3 receptor in mouse fibroblasts. Biochem. Biophys. Res. Commun. 131, 378–385, 1985.

    CAS  PubMed  Google Scholar 

  49. Lee, Y., Inaba, M., DeLuca, H. F. and Mellon, W. S.: Immunological identification of 1, 25-dihydroxyvitamin D3 receptors in human promyelocytic leukemic cells (HL-60) during homologous regulations. J. Biol. Chem. 264, 13701–13705, 1988.

    Google Scholar 

  50. Strom, M., Sandgren, M. E., Brown, T. A. and DeLuca, H. F.: 1, 25-Dihydroxyvitamin D3 up-regulates the 1, 25-dihydroxyvitamin D3 receptorin vivo. Proc. Natl. Acad. Sci. USA 86, 9770–9773, 1989.

    CAS  PubMed  Google Scholar 

  51. Costa, E. M. and Feldman, D.: Homologous up-regulation of the 1, 25 (OH)2 vitamin D3 receptor in rats. Biochem. Biophys. Res. Commun. 137, 742–747, 1986.

    Article  CAS  PubMed  Google Scholar 

  52. Sandgren, M. E. and DeLuca, H. F.: Serum calcium and vitamin D regulate 1, 25-dihydroxyvitamin D3 receptor concentration in rat kidneyin vivo. Proc. Natl. Acad. Sci. USA 87, 4312–4314, 1990.

    CAS  PubMed  Google Scholar 

  53. Desplan, C., Thomasset, M. and Moukhtar, M.: Synthesis, molecular cloning, and restriction analysis of DNA complementary to vitamin D-dependent calcium-binding protein mRNA from rat duodenum. J. Biol. Chem. 258, 2762–2765, 1983.

    CAS  PubMed  Google Scholar 

  54. Darwish, H. M., Krisinger, J., Strom, M. and DeLuca, H. F.: Molecular cloning of the cDNA and chromosomal gene for vitamin D-dependent calcium-bindingprotein of rat intestine. Proc. Natl. Acad. Sci. USA 84, 6108–6111 (1987).

    CAS  PubMed  Google Scholar 

  55. Krisinger, J., Darwish, H., Maeda, N. and DeLuca, H. F.: Structure and nucleotide sequence of the rat intestinal vitamin D-dependent calcium binding protein gene. Proc. Natl. Acad. Sci. USA 85, 8988–8992, 1988.

    CAS  PubMed  Google Scholar 

  56. Perret, C., Lomri, N., Gouhier, N., Auffray, C. and Thomasset, M.: The rat vitamin-D-dependent calcium-binding protein (9-kDa CaBP) gene. Complete nucleotide sequence and structural organization. Eur. J. Biochem. 172, 43–51, 1988.

    Article  CAS  PubMed  Google Scholar 

  57. Darwish, H., Krisinger, J., Furlow, J. D., Smith, C., Murdoch, F. E. and DeLuca, H. F.: An estrogen-responsive element mediates the transcriptional regulation of calbindin D-9K gene in rat uterus. J. Biol. Chem., in press, 1990.

  58. Kerner, S. A., Scott, R. A. and Pike, J. W.: Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3 Proc. Natl. Acad. Sci. USA 86, 4455–4459, 1989.

    CAS  PubMed  Google Scholar 

  59. Demay, M. B., Gerardi, J. M., DeLuca, H. F. and 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. USA 87, 369–373, 1990.

    CAS  PubMed  Google Scholar 

  60. Noda, M., Vogel, R. L., Craig, A. M., Prahl, J., DeLuca, H. F. and Denhardt, D. T.: Identification of a DNA sequence responsible for binding of the 1, 25-dihydroxyvitamin D3 receptor and 1, 25-dihydroxyvitamin D3 enhancementof mouse secreted phosphoprotein 1 (Spp1, osteopontin) gene expression. Proc. Natl. Acad. Sci. USA, in press, 1990.

  61. Schule, R., Umesono, K., Mangelsdorf, D. J., Bolado, J., Pike, J. W. and Evans, R. M.: Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene. Cell 61, 497–504, 1990.

    CAS  PubMed  Google Scholar 

  62. Abe, E., Miyaura, C., Sakagami, H., Takeda, M., Konno, K., Yamazaki, T., Yoshiki, S. and Suda, T.: Differentiation of mouse myeloid leukemia cells induced by 1α, 25-dihydroxyvitamin D3 Proc. Natl. Acad. Sci. USA 78, 4990–4994, 1981.

    CAS  PubMed  Google Scholar 

  63. Tanaka, H., Abe, E., Miyaura, C., Kuribayashi, T., Konno, K., Nishii, Y. and Suda, T.: 1α, 25-Dihydroxycholecalcifrol and a human myeloid leukaemia cell line (HL-60). The presence of a cytosol receptor and induction of differentiation. Biochem. J. 204, 713–719, 1982.

    CAS  PubMed  Google Scholar 

  64. Holick, M. F., Smith, E. and Pincus, S.: Skin as the site of vitamin D synthesis and target tissue for 1, 25-dihydroxyvitamin D3: Use of calcitriol (1, 25-dihydroxyvitamin D3) for treatment of psoriasis. Arch. Dermatol. 123, 1677–1679, 1987.

    Article  CAS  PubMed  Google Scholar 

  65. Smith, E. L., Walworth, N. C. and Holick, M. F.: Effect of 1α,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. J. Invest. Dermatol. 86, 709–714, 1986.

    CAS  PubMed  Google Scholar 

  66. Ostrem, V. K., Lau, W. F., Lee, S. H., Perlman, K., Prahl, J., Schnoes, H. K., DeLuca, H. F. and Ikekawa, N.: Induction of monocytic differentiation of HL-60 cell by 1, 25-dihydroxyvitamin D analogs. J. Biol. Chem. 262, 14164–14171, 1987.

    CAS  PubMed  Google Scholar 

  67. Abe, J., Takita, Y., Nakano, T., Miyaura, C., Suda, T. and Nishii, Y.: A synthetic analogue of vitamin D3, 22-oxa-1α, 25-dihydroxyvitamin D3, is a potent modulator ofin vivo immunoregulating activity without inducing hypercalcemia in mice. Endocrinology 124, 2645–2647, 1989.

    CAS  PubMed  Google Scholar 

  68. Calverley, M. J.: Synthesis of MC903, a biologically active vitamin D metabolite analogue. Tetrahedron Lett. 43, 4609–4619, 1987.

    CAS  Google Scholar 

  69. Krisinger, J., Strom, M., Darwish, H. D., Perlman, K., Smith, C. and DeLuca, H. F.: Induction of calbindin-D 9k mRNA but not calcium transport in rat intestine by 1, 25-dihydroxyvitamin D3-24-homologs. J. Biol. Chem., in press, 1990.

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Wisconsin- Madison, 53706, Madison, Wisconsin

    H. F. DeLuca (Steenbock Research Professor)

Authors
  1. H. F. DeLuca
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

DeLuca, H.F. Recent advances in the molecular mechanism of action of 1, 25-dihydroxyvitamin D3 . J Bone Miner Metab 9, 17–25 (1991). https://doi.org/10.1007/BF02377980

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02377980

Key Words

Search

Navigation