Vitamin D Utilization in Subhuman Primates

  • John S. AdamsEmail author
  • Hong Chen
  • Rene F. Chun
  • Thomas S. Lisse
  • Alejandro Garcia
  • Martin Hewison
Part of the Nutrition and Health book series (NH)


Experiments of nature are crucial for informing scientific discovery. Nearly 30 years ago we began to investigate an outbreak of rachitic bone disease in adolescent New World primates residing at the Los Angeles Zoo. Our investigation of this experiment of nature and that of an adolescent human female with a similar phenotype led us to the discovery of a novel means for relative resistance to vitamin D in primates, including man. We coined this resistance-causing protein the vitamin D response element-binding protein or VDRE-BP for its ability to compete in trans with the liganded vitamin D receptor (VDR) for its cognate response elements. VDRE-BP is now identified as a nucleic acid-binding protein(s) in the heterogeneous nuclear ribonucleoprotein C (hnRNPC) family. The purpose of this review is to examine the role of the VDRE-BP and other associated intracellular proteins that regulate the expression of vitamin D-controlled genes in nonhuman and human primates.


Vitamin D Resistance 1,25-Dihydroxyvitamin D Monkeys Ribonucleoprotein Primate evolution Steroid hormone New World monkeys Vitamin D response element 



This work was supported by National Institutes of Health grants AR37399 and DK58891 to John S. Adams. The authors would like to acknowledge the useful discussions and critiques of this work provided over the years by Dr. Thomas Clemens and the late Dr. Bayard “Skip” Catherwood.


  1. 1.
    Pilbeam D. The descent of hominoids and hominoids and hominoids. Sci Am. 1984;250:84–96.PubMedCrossRefGoogle Scholar
  2. 2.
    Bland Sutton JB. Observation on rickets etc. in wild animals. J Anat. 1884;18:363–97.Google Scholar
  3. 3.
    Krook L, Barrett RB. Simian bone disease—a secondary hyperparathyroidism. Cornell Vet. 1962;52:459–92.PubMedGoogle Scholar
  4. 4.
    Hershkovitz P. Living new world monkeys (Platyrrhini): with an introduction to primates. Chicago, IL: University of Chicago Press; 1977.Google Scholar
  5. 5.
    Jarcho MR, Power ML, Layne-Colon DG, Tardif SD. Digestive efficiency mediated by serum calcium predicts bone mineral density in the common marmoset (Callithrix jacchus). Am J Primatol. 2013;75(2):153–60.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Hunt RD, Garcia FG, Hegsted DM. A comparison of vitamin D2 and D3 in New World primates. I. Production and regression of osteodystrophia fibrosa. Lab Anim Care. 1967;17:222–34.PubMedGoogle Scholar
  7. 7.
    Steenbock H, Kletzein SWF, Halpin JG. Reaction of chicken irradiated ergosterol and irradiated yeast as contrasted with natural vitamin D of fish liver oils. J Biol Chem. 1932;97:249–66.Google Scholar
  8. 8.
    Marx SJ, Jones G, Weinstein RS, Chrousos GP, Renquist DM. Differences in mineral metabolism among nonhuman primates receiving diets with only vitamin D3 or only vitamin D2. J Clin Endocrinol Metab. 1989;69:1282–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Hay AW. The transport of 25-hydroxycholecalciferol in a New World monkey. Biochem J. 1975;151:193–6.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Bouillon R, Van Baelen H, De Moor P. The transport of vitamin D in the serum of primates. Biochem J. 1976;159:463–6.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Teixeira DS, Castro LC, Nóbrega YK, Almeida RC, Gandolfi L, Pratesi R. 25-Hydroxy-vitamin D levels among Callithrix penicillata primate species raised in captivity. J Med Primatol. 2010;39(2):77–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Prado F, Valladares-Padua C. Feeding ecology of a group of black-headed lion tamarin, Leontopithecus caissara (Primates: Callithrichidae), in the Superagui National Park, Southern Brazil. Primatol Brasil. 2004;8:145–54.Google Scholar
  13. 13.
    Correa HKM, Coutinho PEG, Ferrari SF. Between-year differences in the feeding ecology of highland marmosets (Callithrix aurita and Callithrix flaviceps) in southeastern Brazil. J Zool. 2000;252:421–7.CrossRefGoogle Scholar
  14. 14.
    Hilario RR. Padra˜o de actividades, dieta e uso de ha´bitat por Callithrix flaviceps na Reserva Biolo´gica Augusto Ruschi, Santa Teresa, ES, Masters Thesis, Universidade Federal de Minas Gerais. 2008.Google Scholar
  15. 15.
    Porter LM, Garber PA. Mycophagy and its influence on habitat use and ranging patterns in Callimico goeldii. Am J Phys Anthropol. 2010;142(3):468–75.PubMedCrossRefGoogle Scholar
  16. 16.
    Hewison M, Adams JS. Update in vitamin D. J Clin Endocrinol Metab. 2010;95:471–8.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Shinki T, Shiina N, Takahashi Y, Tamoika H, Koizumi H, Suda T. Extremely high circulating levels of 1,25-dihydroxy vitamin D3 in the marmoset, a New World Monkey. Biochem Biophys Res Commun. 1983;114:452–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Adams JS, Gacad MA, Baker AJ, Gonzales B, Rude RK. Serum concentrations of 1,25-dihydroxyvitamin D in Platyrrhini and Catarrhini: a phylogenetic appraisal. Am J Primatol. 1985;9:219–24.CrossRefGoogle Scholar
  19. 19.
    Adams JS, Gacad MA, Rude RK, Endres DB, Mallette LE. Serum concentrations of immunoreactive parathyroid hormone in Platyrrhini and Catarrhini: a comparative analysis with three different antisera. Am J Primatol. 1987;13:425–33.CrossRefGoogle Scholar
  20. 20.
    Adams JS, Gacad MA, Baker AJ, Keuhn G, Rude RK. Diminished internalization and action of 1,25-dihydroxyvitamin D in dermal fibroblasts cultured from New World primates. Endocrinology. 1985;116:2523–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Gacad MA, Adams JS. Evidence for endogenous blockage of cellular 1,25-dihydroxyvitamin D-receptor binding in New World primates. J Clin Invest. 1991;87:996–1001.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Gacad MA, Adams JS. Influence of ultraviolet B radiation on vitamin D3 metabolism in vitamin D3-resistant New World primates. Am J Primatol. 1992;28:263–70.CrossRefGoogle Scholar
  23. 23.
    Brown GM, Grota LJ, Penney DP, Reichlin S. Pituitary-adrenal function in the squirrel monkey. Endocrinology. 1970;86:519–29.PubMedCrossRefGoogle Scholar
  24. 24.
    Brandon DD, Markwick AJ, Chrousos GP, Loriaux DL. Glucocoorticoid resistance in humans and nonhuman primates. Cancer Res. 1989;49:2203–13.Google Scholar
  25. 25.
    Chrousos GP, Brandon D, Renquist DM, et al. Uterine estrogen and progesterone receptors in estrogen and progesterone-resistant primates. J Clin Endocrinol Metab. 1984;58:516–20.PubMedCrossRefGoogle Scholar
  26. 26.
    Albertson BD, Maronian NC, Frederick KL, et al. The effect of ketoconazole on steroidogenesis. II. Adrenocortical enzyme activity in vitro. Res Commun Chem Pathol Pharmacol. 1988;61:27–34.PubMedGoogle Scholar
  27. 27.
    Albertson BD, Frederick KL, Maronian NC, et al. The effect of ketoconazole on steroidogenesis: I. Leydig cell enzyme activity in vitro. Res Commun Chem Pathol Pharmacol. 1988;61:17–26.PubMedGoogle Scholar
  28. 28.
    Moore CC, Mellon SH, Murai J, Siiteri PK, Miller WL. Structure and function of the hepatic form of 11 beta-hydroxysteroid dehydrogenase in the squirrel monkey, an animal model of glucocorticoid resistance. Endocrinology. 1993;133:368–75.PubMedGoogle Scholar
  29. 29.
    Klosterman LL, Murai JT, Siiteri PK. Cortisol levels, binding, and properties of corticosteroidbinding globulin in the serum of primates. Endocrinology. 1986;118:424–34.PubMedCrossRefGoogle Scholar
  30. 30.
    Chrousos GP, Renquist DM, Brandon D, Fowler D, Loriaux DL, Lipsett MB. The squirrel monkey: receptor-mediated end-organ resistant to progesterone? J Clin Endocrinol Metab. 1982;55:364–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Brandon DD, Markwick AJ, Flores M, Dixon K, Albertson BD, Loriaux DL. Genetic variation of the glucocorticoid receptor from a steroid-resistant primate. Mol Endocrinol. 1991;7:89–96.CrossRefGoogle Scholar
  32. 32.
    Scammell JG, Denny WB, Valentine DL, Smith DF. Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. Gen Comp Endocrinol. 2001;124:152–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Stechschulte LA, Sanchez ER. FKBP51-a selective modulator of glucocorticoid and androgen sensitivity. Curr Opin Pharmacol. 2011;11(4):332–7.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Reynolds PD, Ruan Y, Smith DF, Scammell JG. Glucocorticoid resistance in the squirrel monkey is associated with overexpression of the immunophilin FKBP51. J Clin Endocrinol Metab. 1999;84(2):663–9.PubMedGoogle Scholar
  35. 35.
    Davies TH, Ning YM, Sánchez ER. A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J Biol Chem. 2002;277(7):4597–600.PubMedCrossRefGoogle Scholar
  36. 36.
    Liberman UA, de Grange D, Marx SJ. Low affinity of the receptor for 1 alpha, 25-dihydroxyvitamin D3 in the marmoset, a New World monkey. FEBS Lett. 1985;182:385–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Adams JS, Gacad MA. Phenotypic diversity of the cellular 1,25-dihydroxyvitamin D-receptor interaction among different genera of New World primates. J Clin Endocrinol Metab. 1988;66:224–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Gacad MA, Adams JS. Specificity of steroid binding in New World primate cells with a vitamin D-resistant phenotype. Endocrinology. 1992;131:2581–7.PubMedGoogle Scholar
  39. 39.
    Gacad MA, Adams JS. Identification of a competitive binding component in vitamin D-resistant New World primate cells with a low affinity but high capacity for 1,25-dihydroxyvitmain D3. J Bone Miner Res. 1993;8:27–35.PubMedCrossRefGoogle Scholar
  40. 40.
    Chun RF, Chen H, Boldrick L, Sweet C, Adams JS. Cloning, sequencing and functional characterization of the vitamin D receptor in vitamin D-resistant New World primates. Am J Primates. 2001;54:107–18.CrossRefGoogle Scholar
  41. 41.
    Arbelle JE, Chen H, Gacad MA, Allegretto EA, Pike JW, Adams JS. Inhibition of vitamin D receptor-retinoid X receptor-vitamin D response element complex formation by nuclear extracts of vitamin D-resistant New World primate cells. Endocrinology. 1996;137:786–9.PubMedGoogle Scholar
  42. 42.
    Chen H, Arbelle JE, Gacad MA, Allegretto EA, Adams JS. Vitamin D and gonadal steroid-resistant New World primate cells express an intracellular protein which competes with the estrogen receptor for binding to the estrogen response element. J Clin Invest. 1997;99:769–75.Google Scholar
  43. 43.
    Chen H, Hu B, Allegretto EA, Adams JS. The vitamin D response element binding proteins: novel dominant-negative-acting regulators of vitamin D-directed transactivation. J Biol Chem. 2000;275:35557–64.PubMedCrossRefGoogle Scholar
  44. 44.
    Chen H, Hewison M, Hu B, Adams JS. Heterogeneous nuclear ribonucleoprotein (hnRNP)-binding to hormone response elements: a cause of vitamin D resistance. Proc Natl Acad Sci U S A. 2003;100:6109–14.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Adams JS, Chen H, Chun R, Gacad MA, Encinas C, Ren S, Nguyen L, Wu S. Hewison, Barsony J. Response element binding proteins and intracellular vitamin D binding proteins: novel regulators of vitamin D trafficking, action and metabolism. J Ster Biochem Mol Biol. 2004;89–90:461–5.CrossRefGoogle Scholar
  46. 46.
    Dreyfuss G, Matunis MJ, Pinol-Roma S, Burd CG. hnRNP proteins and the biogenesis of mRNA. Annu Rev Biochem. 1993;62:289–321.PubMedCrossRefGoogle Scholar
  47. 47.
    Chen H, Hewison M, Adams JS. Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel response element-binding protein. J Biol Chem. 2006;281:39114–20.PubMedCrossRefGoogle Scholar
  48. 48.
    Lisse TS, Hewison M, Adams JS. Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling. Steroids. 2011;76(4):331–9.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Horwitz KB, Jackson TA, Bain DL, Richer JK, Takamoto GS, Tung L. Nuclear receptors coactivators and corepressors. Mol Endocrinol. 1996;10:1167–77.PubMedGoogle Scholar
  50. 50.
    Chen H, Stuart W, Hu B, Nguyen L, Huang G, Clemens TL, Adams JS. Creation of estrogen resistance in vivo by transgenic overexpression of the heterogeneous nuclear ribonucleoprotein-related estrogen response element binding protein. Endocrinology. 2005;146:4266–73.PubMedCrossRefGoogle Scholar
  51. 51.
    Chen H, Hewison M, Adams JS. Control of estradiol-directed gene transactivation by an intracellular estrogen-binding protein and an estrogen response element-binding protein. Mol Endocrinol. 2008;22:559–69.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Chen H, Clemens TL, Hewison M, Adams JS. Estradiol and tamoxifen mediate rescue of the dominant-negative effects of estrogen response element-binding protein in vivo and in vitro. Endocrinology. 2009;150:2429–35.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Chen H, Gilbert LC, Lu X, Liu Z, You S, Weitzmann MN, Nanes MS, Adams JS. Estrogen response element binding protein stimulates osteoclastogenesis and bone resorption. J Bone Min Res. 2011;26:2537–47.CrossRefGoogle Scholar
  54. 54.
    Gacad MA, LeBon TR, Chen H, Arbelle JE, Adams JS. Functional characterization and purification of an intracellular vitamin D binding protein in vitamin D resistant New World primate cells: amino acid sequence homology with proteins in the hsp-70 family. J Biol Chem. 1997;272:8433–40.PubMedCrossRefGoogle Scholar
  55. 55.
    Gacad MA, Adams JS. Proteins in the heat shock-70 family specifically bind 25-hydroxylated vitamin D metabolites and 17β-estradiol. J Clin Endocrinol Metab. 1998;83:1264–7.PubMedGoogle Scholar
  56. 56.
    Hartl FU. Molecular chaperones in cellular protein folding. Nature. 1996;3381:571–9.CrossRefGoogle Scholar
  57. 57.
    Wu S, Ren S-Y, Gacad MA, Adams JS. Intracellular vitamin D binding proteins: novel facilitators of vitamin D-directed transactivation. Mol Endocrinol. 2000;14:1387–97.PubMedCrossRefGoogle Scholar
  58. 58.
    Wu S, Chun R, Ren S, Chen H, Adams JS. Regulation of 1,25-dihydroxyvitamin D synthesis by intracellular vitamin D binding protein-1. Endocrinology. 2002;143:4135–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Christensen EI, Willnow TE. Essential role of megalin in renal proximal tubule for vitamin homeostasis. J Am Soc Nephrol. 1999;10:2224–36.PubMedGoogle Scholar
  60. 60.
    Nykjaer A, Dragun D, Walther D, et al. An endocytic pathway essential for renal uptake and activation of the steroid 25(OH) vitamin D3. Cell. 1999;96:507–15.PubMedCrossRefGoogle Scholar
  61. 61.
    Chun R, Gacad MA, Hewison M, Adams JS. Adenosine 5’-triphosphate-dependent vitamin D sterol binding to heat shock protein-70 chaperones. Endocrinology. 2005;146:5540–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Adams JS. “Bound” to work: the free hormone hypothesis revisited. Cell. 2005;122:647–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Adams JS, Chen H, Chun RF, Nguyen L, Wu S, Ren SY, Barsony J, Gacad MA. Novel regulators of vitamin D action and metabolism: lessons learned at the Los Angeles Zoo. J Cell Biol. 2003;88:308–14.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • John S. Adams
    • 1
    • 2
    Email author
  • Hong Chen
    • 3
  • Rene F. Chun
    • 1
  • Thomas S. Lisse
    • 4
  • Alejandro Garcia
    • 1
  • Martin Hewison
    • 1
    • 2
  1. 1.Orthopaedic Hospital Research CenterUniversity of California Los AngelesLos AngelesUSA
  2. 2.Molecular Biology InstituteUniversity of California Los AngelesLos AngelesUSA
  3. 3.Veterans Administration Medical Center and Division of Endocrinology, Metabolism, and Lipids, Department of MedicineEmory University School of MedicineAtlantaUSA
  4. 4.Endocrine UnitMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

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