Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

New aspects of vitamin D metabolism and action — addressing the skin as source and target

Nature Reviews Endocrinology volume 16, pages 234–252 (2020)Cite this article

Subjects

Abstract

Vitamin D has a key role in stimulating calcium absorption from the gut and promoting skeletal health, as well as many other important physiological functions. Vitamin D is produced in the skin. It is subsequently metabolized to its hormonally active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), by the 1-hydroxylase and catabolized by the 24-hydroxylase. In this Review, we pay special attention to the effect of mutations in these enzymes and their clinical manifestations. We then discuss the role of vitamin D binding protein in transporting vitamin D and its metabolites from their source to their targets, the free hormone hypothesis for cell entry and HSP70 for intracellular transport. This is followed by discussion of the vitamin D receptor (VDR) that mediates the cellular actions of 1,25(OH)2D. Cell-specific recruitment of co-regulatory complexes by liganded VDR leads to changes in gene expression that result in distinct physiological actions by 1,25(OH)2D, which are disrupted by mutations in the VDR. We then discuss the epidermis and hair follicle, to provide a non-skeletal example of a tissue that expresses VDR that not only makes vitamin D but also can metabolize it to its hormonally active form. This enables vitamin D to regulate epidermal differentiation and hair follicle cycling and, in so doing, to promote barrier function, wound healing and hair growth, while limiting cancer development.

Key points

  • Mutations in the enzymes involved in vitamin D metabolism cause human diseases such as rickets.

  • Vitamin D binding protein is the major transport protein for vitamin D metabolites, but with the exception of a few tissues such as the kidney, it is the free forms of these metabolites that enter cells.

  • The vitamin D receptor (VDR) is the major mediator of vitamin D biological action.

  • VDR binding sites can be located in a range of locations including introns and at distal intergenic regions of regulated genes.

  • Co-regulators of VDR provide cell-specific genomic regulation.

  • The skin is an excellent non-skeletal model for the study of vitamin D as it is the source of vitamin D, contains the vitamin D-metabolizing enzymes and expresses the VDR, making it a target tissue as well.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Vitamin D production and metabolism.
Fig. 2: Transport of 25OHD between and within cells.
Fig. 3: VDR–RXRα vitamin D receptor binding site (DR3) model.
Fig. 4: The four layers of the epidermis, their distinct functions and location of major VDR co-regulators.

Similar content being viewed by others

References

  1. Bikle, D. D. Vitamin D and the skin: physiology and pathophysiology. Rev. Endocr. Metab. Disord. 13, 3–19 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jäpelt, R. B. & Jakob sen, J. Vitamin D in plants: a review of occurrence, analysis, and biosynthesis. Front. Plant. Sci. 4, 136 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tripkovic, L. et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am. J. Clin. Nutr. 95, 1357–1364 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tian, X. Q. & Holick, M. F. Catalyzed thermal isomerization between previtamin D3 and vitamin D3 via β-cyclodextrin complexation. J. Biol. Chem. 270, 8706–8711 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Passeron, T. et al. Sunscreen photoprotection and vitamin D status. Br. J. Dermatol. 181, 916–931 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Prabhu, A. V., Luu, W., Li, D., Sharpe, L. J. & Brown, A. J. DHCR7: a vital enzyme switch between cholesterol and vitamin D production. Prog. Lipid Res. 64, 138–151 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Bijlsma, M. F. et al. Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLOS Biol. 4, e232 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bhattacharyya, M. H. & DeLuca, H. F. Subcellular location of rat liver calciferol-25-hydroxylase. Arch. Biochem. Biophys. 160, 58–62 (1974).

    Article  CAS  PubMed  Google Scholar 

  9. Horst, R. L., Littledike, E. T., Riley, J. L. & Napoli, J. L. Quantitation of vitamin D and its metabolites and their plasma concentrations in five species of animals. Anal. Biochem. 116, 189–203 (1981).

    Article  CAS  PubMed  Google Scholar 

  10. Zhu, J. G., Ochalek, J. T., Kaufmann, M., Jones, G. & Deluca, H. F. CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc. Natl Acad. Sci. USA 110, 15650–15655 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cheng, J. B., Levine, M. A., Bell, N. H., Mangelsdorf, D. J. & Russell, D. W. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc. Natl Acad. Sci. USA 101, 7711–7715 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bikle, D. D., Patzek, S. & Wang, Y. Physiologic and pathophysiologic roles of extra renal CYP27b1: case report and review. Bone Rep. 8, 255–267 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Thacher, T. D., Fischer, P. R., Singh, R. J., Roizen, J. & Levine, M. A. CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an atypical form of vitamin D deficiency. J. Clin. Endocrinol. Metab. 100, E1005–E1013 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Fu, G. K. et al. Cloning of human 25-hydroxyvitamin D-1α-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol. Endocrinol. 11, 1961–1970 (1997).

    CAS  PubMed  Google Scholar 

  15. Schlingmann, K. P. et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N. Engl. J. Med. 365, 410–421 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Bikle, D. D., Siiteri, P. K., Ryzen, E. & Haddad, J. G. Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J. Clin. Endocrinol. Metab. 61, 969–975 (1985).

    Article  CAS  PubMed  Google Scholar 

  17. Bikle, D. D. et al. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J. Clin. Endocrinol. Metab. 63, 954–959 (1986).

    Article  CAS  PubMed  Google Scholar 

  18. Malik, S. et al. Common variants of the vitamin D binding protein gene and adverse health outcomes. Crit. Rev. Clin. Lab. Sci. 50, 1–22 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bikle, D. D. & Schwartz, J. Vitamin D binding protein, total and free vitamin D levels in different physiological and pathophysiological conditions. Front. Endocrinol. 10, 317 (2019).

    Article  Google Scholar 

  20. Bikle, D. D., Malmstroem, S. & Schwartz, J. Current Controversies: are free vitamin metabolite levels a more accurate assessment of vitamin D status than total levels? Endocrinol. Metab. Clin. North Am. 46, 901–918 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Safadi, F. F. et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J. Clin. Invest. 103, 239–251 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Henderson, C. M. et al. Vitamin D-binding protein deficiency and homozygous deletion of the GC gene. N. Engl. J. Med. 380, 1150–1157 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu, S. et al. Intracellular vitamin D binding proteins: novel facilitators of vitamin D-directed transactivation. Mol. Endocrinol. 14, 1387–1397 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Khanal, R. & Nemere, I. Membrane receptors for vitamin D metabolites. Crit. Rev. Eukaryot. Gene Expr. 17, 31–47 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Pike, J. W., Meyer, M. B. & Bishop, K. A. Regulation of target gene expression by the vitamin D receptor - an update on mechanisms. Rev. Endocr. Metab. Disord. 13, 45–55 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Demay, M. B. The hair cycle and vitamin D receptor. Arch. Biochem. Biophys. 523, 19–21 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Meyer, M. B. et al. A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation. J. Biol. Chem. 292, 17541–17558 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meyer, M. B. et al. A chromatin-based mechanism controls differential regulation of the cytochrome P450 gene Cyp24a1 in renal and non-renal tissues. J. Biol. Chem. 294, 14467–14481 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Meyer, M. B., Benkusky, N. A., Lee, C. H. & Pike, J. W. Genomic determinants of gene regulation by 1,25-dihydroxyvitamin D3 during osteoblast-lineage cell differentiation. J. Biol. Chem. 289, 19539–19554 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Malloy, P. J. et al. Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets. Mol. Genet. Metab. 111, 33–40 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Bikle, D. D. Vitamin D metabolism and function in the skin. Mol. Cell. Endocrinol. 347, 80–89 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Barrea, L. et al. Vitamin D and its role in psoriasis: an overview of the dermatologist and nutritionist. Rev. Endocr. Metab. Disord. 18, 195–205 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mitsche, M. A., McDonald, J. G., Hobbs, H. H. & Cohen, J. C. Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways. eLife 4, e07999 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Prabhu, A. V., Luu, W., Sharpe, L. J. & Brown, A. J. Cholesterol-mediated degradation of 7-dehydrocholesterol reductase switches the balance from cholesterol to vitamin D synthesis. J. Biol. Chem. 291, 8363–8373 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Prabhu, A. V., Luu, W., Sharpe, L. J. & Brown, A. J. Phosphorylation regulates activity of 7-dehydrocholesterol reductase (DHCR7), a terminal enzyme of cholesterol synthesis. J. Steroid Biochem. Mol. Biol. 165, 363–368 (2017).

    Article  CAS  PubMed  Google Scholar 

  36. Tint, G. S. et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N. Engl. J. Med. 330, 107–113 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Xu, G. et al. Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Opitz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats. J. Clin. Invest. 95, 76–81 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Movassaghi, M., Bianconi, S., Feinn, R., Wassif, C. A. & Porter, F. D. Vitamin D levels in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. A 173, 2577–2583 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ahn, J. et al. Genome-wide association study of circulating vitamin D levels. Hum. Mol. Genet. 19, 2739–2745 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, T. J. et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376, 180–188 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kuan, V., Martineau, A. R., Griffiths, C. J., Hypponen, E. & Walton, R. DHCR7 mutations linked to higher vitamin D status allowed early human migration to northern latitudes. BMC Evol. Biol. 13, 144 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhu, J. & DeLuca, H. F. Vitamin D 25-hydroxylase - four decades of searching, are we there yet? Arch. Biochem. Biophys. 523, 30–36 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Moghadasian, M. H. Cerebrotendinous xanthomatosis: clinical course, genotypes and metabolic backgrounds. Clin. Invest. Med. 27, 42–50 (2004).

    CAS  PubMed  Google Scholar 

  44. Cheng, J. B., Motola, D. L., Mangelsdorf, D. J. & Russell, D. W. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxylase. J. Biol. Chem. 278, 38084–38093 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Al Mutair, A. N., Nasrat, G. H. & Russell, D. W. Mutation of the CYP2R1 vitamin D 25-hydroxylase in a Saudi Arabian family with severe vitamin D deficiency. J. Clin. Endocrinol. Metab. 97, E2022–E2025 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Molin, A. et al. Vitamin D-dependent rickets type 1B (25-hydroxylase deficiency): a rare condition or a misdiagnosed condition? J. Bone Miner. Res. 32, 1893–1899 (2017).

    Article  CAS  PubMed  Google Scholar 

  47. Gupta, R. P., Hollis, B. W., Patel, S. B., Patrick, K. S. & Bell, N. H. CYP3A4 is a human microsomal vitamin D 25-hydroxylase. J. Bone Miner. Res. 19, 680–688 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Gupta, R. P., He, Y. A., Patrick, K. S., Halpert, J. R. & Bell, N. H. CYP3A4 is a vitamin D-24- and 25-hydroxylase: analysis of structure function by site-directed mutagenesis. J. Clin. Endocrinol. Metab. 90, 1210–1219 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Roizen, J. D. et al. CYP3A4 mutation causes vitamin D-dependent rickets type 3. J. Clin. Invest. 128, 1913–1918 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Adams, J. S. et al. Regulation of the extrarenal CYP27B1-hydroxylase. J. Steroid Biochem. Mol. Biol. 144, 22–27 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Tebben, P. J., Singh, R. J. & Kumar, R. Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment. Endocr. Rev. 37, 521–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fraser, D. et al. Pathogenesis of hereditary vitamin-D-dependent rickets — an inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1α,25-dihydroxyvitamin D. N. Engl. J. Med. 289, 817–822 (1973).

    Article  CAS  PubMed  Google Scholar 

  53. Scriver, C. R., Reade, T. M., DeLuca, H. F. & Hamstra, A. J. Serum 1,25-dihydroxyvitamin D levels in normal subjects and in patients with hereditary rickets or bone disease. N. Engl. J. Med. 299, 976–979 (1978).

    Article  CAS  PubMed  Google Scholar 

  54. Delvin, E. E., Glorieux, F. H., Marie, P. J. & Pettifor, J. M. Vitamin D dependency: replacement therapy with calcitriol? J. Pediatr. 99, 26–34 (1981).

    Article  CAS  PubMed  Google Scholar 

  55. St-Arnaud, R., Messerlian, S., Moir, J. M., Omdahl, J. L. & Glorieux, F. H. The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. J. Bone Miner. Res. 12, 1552–1559 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Takeyama, K. et al. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science 277, 1827–1830 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Monkawa, T. et al. Molecular cloning of cDNA and genomic DNA for human 25-hydroxyvitamin D31α-hydroxylase. Biochem. Biophys. Res. Commun. 239, 527–533 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Kim, C. J. et al. Vitamin D 1α-hydroxylase gene mutations in patients with 1α-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 92, 3177–3182 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Glorieux, F. H. & Pettifor, J. M. Vitamin D/dietary calcium deficiency rickets and pseudo-vitamin D deficiency rickets. Bonekey Rep. 3, 524 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bitzan, M. & Goodyer, P. R. Hypophosphatemic rickets. Pediatr. Clin. North Am. 66, 179–207 (2019).

    Article  PubMed  Google Scholar 

  61. Xu, Y. et al. Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1α,25-dihydroxyvitamin D3: implications for drug-induced osteomalacia. Mol. Pharmacol. 69, 56–65 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Prosser, D. E., Kaufmann, M., O'Leary, B., Byford, V. & Jones, G. Single A326G mutation converts human CYP24A1 from 25-OH-D3-24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH)2D3-26,23-lactone. Proc. Natl Acad. Sci. USA 104, 12673–12678 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jones, G., Prosser, D. E. & Kaufmann, M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch. Biochem. Biophys. 523, 9–18 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Brodie, M. J. et al. Effect of rifampicin and isoniazid on vitamin D metabolism. Clin. Pharmacol. Ther. 32, 525–530 (1982).

    Article  CAS  PubMed  Google Scholar 

  65. Sakaki, T. et al. Dual metabolic pathway of 25-hydroxyvitamin D3 catalyzed by human CYP24. Eur. J. Biochem. 267, 6158–6165 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Harant, H., Spinner, D., Reddy, G. S. & Lindley, I. J. Natural metabolites of 1α,25-dihydroxyvitamin D3 retain biologic activity mediated through the vitamin D receptor. J. Cell. Biochem. 78, 112–120 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Martineau, C. et al. Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2. J. Clin. Invest. 128, 3546–3557 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Plachot, J. J. et al. In vitro action of 1,25-dihydroxycholecalciferol and 24,25- dihydroxycholecalciferol on matrix organization and mineral distribution in rabbit growth plate. Metab. Bone Dis. Relat. Res. 4, 135–142 (1982).

    Article  CAS  PubMed  Google Scholar 

  69. St-Arnaud, R. et al. Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D. Endocrinology 141, 2658–2666 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Jones, G., Kottler, M. L. & Schlingmann, K. P. Genetic diseases of vitamin D metabolizing enzymes. Endocrinol. Metab. Clin. North Am. 46, 1095–1117 (2017).

    Article  PubMed  Google Scholar 

  71. Dinour, D. et al. Maternal and infantile hypercalcemia caused by vitamin-D-hydroxylase mutations and vitamin D intake. Pediatr. Nephrol. 30, 145–152 (2015).

    Article  PubMed  Google Scholar 

  72. Shah, A. D. et al. Maternal hypercalcemia due to failure of 1,25-dihydroxyvitamin-D3 catabolism in a patient with CYP24A1 mutations. J. Clin. Endocrinol. Metab. 100, 2832–2836 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tebben, P. J. et al. Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy. J. Clin. Endocrinol. Metab. 97, E423–E427 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cools, M. et al. Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: a cross-sectional study. Bone 81, 89–96 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Molin, A. et al. CYP24A1 mutations in a cohort of hypercalcemic patients: evidence for a recessive trait. J. Clin. Endocrinol. Metab. 100, E1343–E1352 (2015).

    Article  CAS  PubMed  Google Scholar 

  76. Lightwood, R. & Stapleton, T. Idiopathic hypercalcaemia in infants. Lancet 265, 255–256 (1953).

    Article  CAS  PubMed  Google Scholar 

  77. Pober, B. R. Williams-Beuren syndrome. N. Engl. J. Med. 362, 239–252 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, A. et al. Description of 5 novel SLC34A3/NPT2c mutations causing hereditary hypophosphatemic rickets with hypercalciuria. Kidney Int. Rep. 4, 1179–1186 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Bergwitz, C. & Miyamoto, K. I. Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflugers Arch. 471, 149–163 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Kaufmann, M. et al. Clinical utility of simultaneous quantitation of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by LC-MS/MS involving derivatization with DMEQ-TAD. J. Clin. Endocrinol. Metab. 99, 2567–2574 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hirschfeld, J. Immune-electrophoretic demonstration of qualitative differences in human sera and their relation to the haptoglobins. Acta Pathol. Microbiol. Scand. 47, 160–168 (1959).

    Article  CAS  PubMed  Google Scholar 

  82. Daiger, S. P., Schanfield, M. S. & Cavalli-Sforza, L. L. Group-specific component (Gc) proteins bind vitamin D and 25-hydroxyvitamin D. Proc. Natl Acad. Sci. USA 72, 2076–2080 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Armas, L. A., Hollis, B. W. & Heaney, R. P. Vitamin D2 is much less effective than vitamin D3 in humans. J. Clin. Endocrinol. Metab. 89, 5387–5391 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Mendel, C. M. The free hormone hypothesis: a physiologically based mathematical model. Endocr. Rev. 10, 232–274 (1989).

    Article  CAS  PubMed  Google Scholar 

  85. Nykjaer, A. et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96, 507–515 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Zella, L. A., Shevde, N. K., Hollis, B. W., Cooke, N. E. & Pike, J. W. Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology 149, 3656–3667 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cooke, N. E., McLeod, J. F., Wang, X. K. & Ray, K. Vitamin D binding protein: genomic structure, functional domains, and mRNA expression in tissues. J. Steroid Biochem. Mol. Biol. 40, 787–793 (1991).

    Article  CAS  PubMed  Google Scholar 

  88. Hagenfeldt, Y., Carlstrom, K., Berlin, T. & Stege, R. Effects of orchidectomy and different modes of high dose estrogen treatment on circulating “free” and total 1,25-dihydroxyvitamin D in patients with prostatic cancer. J. Steroid Biochem. Mol. Biol. 39, 155–159 (1991).

    Article  CAS  PubMed  Google Scholar 

  89. Moller, U. K., Streym, S., Heickendorff, L., Mosekilde, L. & Rejnmark, L. Effects of 25OHD concentrations on chances of pregnancy and pregnancy outcomes: a cohort study in healthy Danish women. Eur. J. Clin. Nutr. 66, 862–868 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Zhang, J. Y., Lucey, A. J., Horgan, R., Kenny, L. C. & Kiely, M. Impact of pregnancy on vitamin D status: a longitudinal study. Br. J. Nutr. 112, 1081–1087 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Moller, U. K. et al. Increased plasma concentrations of vitamin D metabolites and vitamin D binding protein in women using hormonal contraceptives: a cross-sectional study. Nutrients 5, 3470–3480 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Guha, C., Osawa, M., Werner, P. A., Galbraith, R. M. & Paddock, G. V. Regulation of human Gc (vitamin D–binding) protein levels: hormonal and cytokine control of gene expression in vitro. Hepatology 21, 1675–1681 (1995).

    CAS  PubMed  Google Scholar 

  93. Dahl, B. et al. Trauma stimulates the synthesis of Gc-globulin. Intensive Care Med. 27, 394–399 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Schiodt, F. V. Gc-globulin in liver disease. Dan. Med. Bull. 55, 131–146 (2008).

    PubMed  Google Scholar 

  95. Wang, X., Shapses, S. A. & Al-Hraishawi, H. Free and bioavailable 25-hydroxyvitamin D levels in patients with primary hyperparathyroidism. Endocr. Pract. 23, 66–71 (2017).

    Article  PubMed  Google Scholar 

  96. Song, Y. H., Ray, K., Liebhaber, S. A. & Cooke, N. E. Vitamin D-binding protein gene transcription is regulated by the relative abundance of hepatocyte nuclear factors 1α and 1β. J. Biol. Chem. 273, 28408–28418 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Cleve, H. & Constans, J. The mutants of the vitamin-D-binding protein: more than 120 variants of the GC/DBP system. Vox Sang. 54, 215–225 (1988).

    Article  CAS  PubMed  Google Scholar 

  98. Chun, R. F. New perspectives on the vitamin D binding protein. Cell Biochem. Funct. 30, 445–456 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Nagasawa, H. et al. Gc protein (vitamin D-binding protein): Gc genotyping and GcMAF precursor activity. Anticancer Res. 25, 3689–3695 (2005).

    CAS  PubMed  Google Scholar 

  100. Uto, Y. et al. β-Galactosidase treatment is a common first-stage modification of the three major subtypes of Gc protein to GcMAF. Anticancer Res. 32, 2359–2364 (2012).

    CAS  PubMed  Google Scholar 

  101. Arnaud, J. & Constans, J. Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum. Genet. 92, 183–188 (1993).

    Article  CAS  PubMed  Google Scholar 

  102. Bouillon, R., van Baelen, H. & de Moor, P. Comparative study of the affinity of the serum vitamin D-binding protein. J. Steroid Biochem. 13, 1029–1034 (1980).

    Article  CAS  PubMed  Google Scholar 

  103. Boutin, B., Galbraith, R. M. & Arnaud, P. Comparative affinity of the major genetic variants of human group-specific component (vitamin D-binding protein) for 25-(OH) vitamin D. J. Steroid Biochem. 32, 59–63 (1989).

    Article  CAS  PubMed  Google Scholar 

  104. Jones, K. S. et al. 25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype. J. Clin. Endocrinol. Metab. 99, 3373–3381 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chun, R. F. et al. Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J. Clin. Endocrinol. Metab. 95, 3368–3376 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bikle, D. D., Gee, E., Halloran, B. & Haddad, J. G. Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease. J. Clin. Invest. 74, 1966–1971 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Schwartz, J. B. et al. A comparison of measured and calculated free 25(OH) vitamin D levels in clinical populations. J. Clin. Endocrinol. Metab. 99, 1631–1637 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Bikle, D. D., Halloran, B. P., Gee, E., Ryzen, E. & Haddad, J. G. Free 25-hydroxyvitamin D levels are normal in subjects with liver disease and reduced total 25-hydroxyvitamin D levels. J. Clin. Invest. 78, 748–752 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Schwartz, J. B. et al. Determination of free 25(OH)D concentrations and their relationships to total 25(OH)D in multiple clinical populations. J. Clin. Endocrinol. Metab. 103, 3278–3288 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Schwartz, J. B., Kane, L. & Bikle, D. Response of vitamin D concentration to vitamin D3 administration in older adults without sun exposure: a randomized double-blind trial. J. Am. Geriatr. Soc. 64, 65–72 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Lauridsen, A. L., Vestergaard, P. & Nexo, E. Mean serum concentration of vitamin D-binding protein (Gc globulin) is related to the Gc phenotype in women. Clin. Chem. 47, 753–756 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Hoofnagle, A. N., Eckfeldt, J. H. & Lutsey, P. L. Vitamin D-binding protein concentrations quantified by mass spectrometry. N. Engl. J. Med. 373, 1480–1482 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Carpenter, T. O. et al. Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers. J. Bone Miner. 28, 213–221 (2013).

    Article  CAS  Google Scholar 

  114. Santos, B. R., Mascarenhas, L. P., Boguszewski, M. C. & Spritzer, P. M. Variations in the vitamin D-binding protein (DBP) gene are related to lower 25-hydroxyvitamin D levels in healthy girls: a cross-sectional study. Horm. Res. Paediatr. 79, 162–168 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Sollid, S. T. et al. Effects of vitamin D binding protein phenotypes and vitamin D supplementation on serum total 25(OH)D and directly measured free 25(OH)D. Eur. J. Endocrinol 174, 445–452 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Takiar, R. et al. The associations of 25-hydroxyvitamin D levels, vitamin D binding protein gene polymorphisms, and race with risk of incident fracture-related hospitalization: twenty-year follow-up in a bi-ethnic cohort (the ARIC study). Bone 78, 94–101 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Leong, A. et al. The causal effect of vitamin D binding protein (DBP) levels on calcemic and cardiometabolic diseases: a Mendelian randomization study. PLOS Med. 11, e1001751 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Hirai, M. et al. Group specific component protein genotype is associated with NIDDM in Japan. Diabetologia 41, 742–743 (1998).

    Article  CAS  PubMed  Google Scholar 

  119. Baier, L. J., Dobberfuhl, A. M., Pratley, R. E., Hanson, R. L. & Bogardus, C. Variations in the vitamin D-binding protein (Gc locus) are associated with oral glucose tolerance in nondiabetic Pima Indians. J. Clin. Endocrinol. Metab. 83, 2993–2996 (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Ye, W. Z., Dubois-Laforgue, D., Bellanne-Chantelot, C., Timsit, J. & Velho, G. Variations in the vitamin D-binding protein (Gc locus) and risk of type 2 diabetes mellitus in French Caucasians. Metabolism 50, 366–369 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Lauridsen, A. L. et al. Female premenopausal fracture risk is associated with Gc phenotype. J. Bone Miner. 19, 875–881 (2004).

    Article  Google Scholar 

  122. Papiha, S. S., Allcroft, L. C., Kanan, R. M., Francis, R. M. & Datta, H. K. Vitamin D binding protein gene in male osteoporosis: association of plasma DBP and bone mineral density with (TAAA)(n)-Alu polymorphism in DBP. Calcif. Tissue Int. 65, 262–266 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Ezura, Y. et al. Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density. J. Bone Miner. Res. 18, 1642–1649 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Chishimba, L., Thickett, D. R., Stockley, R. A. & Wood, A. M. The vitamin D axis in the lung: a key role for vitamin D-binding protein. Thorax 65, 456–462 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Faserl, K. et al. Polymorphism in vitamin D-binding protein as a genetic risk factor in the pathogenesis of endometriosis. J. Clin. Endocrinol. Metab. 96, E233–E241 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Eloranta, J. J. et al. Association of a common vitamin D-binding protein polymorphism with inflammatory bowel disease. Pharmacogenet Genomics 21, 559–564 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Abbas, S. et al. The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status. Cancer Epidemiol. Biomarkers Prev. 17, 1339–1343 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Dimopoulos, M. A. et al. Genetic markers in carcinoma of the prostate. Eur. Urol. 10, 315–316 (1984).

    Article  CAS  PubMed  Google Scholar 

  129. Zhou, L. et al. GC Glu416Asp and Thr420Lys polymorphisms contribute to gastrointestinal cancer susceptibility in a Chinese population. Int. J. Clin. Exp. Med. 5, 72–79 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Poynter, J. N. et al. Genetic variation in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC) and risk for colorectal cancer: results from the Colon Cancer Family Registry. Cancer Epidemiol. Biomarkers Prev. 19, 525–536 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Martineau, A. R. et al. Association between Gc genotype and susceptibility to TB is dependent on vitamin D status. Eur. Respir. J. 35, 1106–1112 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Gacad, M. A., Chen, H., Arbelle, J. E., LeBon, T. & Adams, J. S. 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. 272, 8433–8440 (1997).

    Article  CAS  PubMed  Google Scholar 

  133. Adams, J. S. et al. Response element binding proteins and intracellular vitamin D binding proteins: novel regulators of vitamin D trafficking, action and metabolism. J. Steroid Biochem. Mol. Biol. 89-90, 461–465 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Brumbaugh, P. F. & Haussler, M. R. 1α,25-Dihydroxycholecalciferol receptors in intestine. II. Temperature-dependent transfer of the hormone to chromatin via a specific cytosol receptor. J. Biol. Chem. 249, 1258–1262 (1974).

    CAS  PubMed  Google Scholar 

  135. Wang, Y., Zhu, J. & DeLuca, H. F. Where is the vitamin D receptor? Arch. Biochem. Biophys. 523, 123–133 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Christakos, S., Dhawan, P., Verstuyf, A., Verlinden, L. & Carmeliet, G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol. Rev. 96, 365–408 (2016).

    Article  CAS  PubMed  Google Scholar 

  137. Gunton, J. E. & Girgis, C. M. Vitamin D and muscle. Bone Rep. 8, 163–167 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Zheng, J. et al. HDX reveals the conformational dynamics of DNA sequence specific VDR co-activator interactions. Nat. Commun. 8, 923 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Shaffer, P. L. & Gewirth, D. T. Structural basis of VDR-DNA interactions on direct repeat response elements. EMBO J. 21, 2242–2252 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Rochel, N., Wurtz, J. M., Mitschler, A., Klaholz, B. & Moras, D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol. Cell 5, 173–179 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Carlberg, C., Molnár, F. & Mouriño, A. Vitamin D receptor ligands: the impact of crystal structures. Expert. Opin. Ther. Pat. 22, 417–435 (2012).

    Article  CAS  PubMed  Google Scholar 

  142. Mizwicki, M. T. & Norman, A. W. The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling. Sci. Signal. 2, re4 (2009).

    Article  CAS  PubMed  Google Scholar 

  143. Singarapu, K. K. et al. Ligand-specific structural changes in the vitamin D receptor in solution. Biochemistry 50, 11025–11033 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Rochel, N. et al. Common architecture of nuclear receptor heterodimers on DNA direct repeat elements with different spacings. Nat. Struct. Mol. Biol. 18, 564–570 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Orlov, I., Rochel, N., Moras, D. & Klaholz, B. P. Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA. EMBO J. 31, 291–300 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Zhang, J. et al. DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nat. Struct. Mol. Biol. 18, 556–563 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Feldman, D. & Malloy, P. J. Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets. Bonekey Rep. 3, 510 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Lee, S. M., Goellner, J. J., O'Brien, C. A. & Pike, J. W. A humanized mouse model of hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. Endocrinology 155, 4137–4148 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Huet, T. et al. A vitamin D receptor selectively activated by gemini analogs reveals ligand dependent and independent effects. Cell Rep. 10, 516–526 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Lee, S. M. & Pike, J. W. The vitamin D receptor functions as a transcription regulator in the absence of 1,25-dihydroxyvitamin D3. J. Steroid Biochem. Mol. Biol. 164, 265–270 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. Balsan, S. et al. Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D. J. Clin. Invest. 77, 1661–1667 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chaturvedi, D., Garabedian, M., Carel, J. C. & Leger, J. Different mechanisms of intestinal calcium absorption at different life stages: therapeutic implications and long-term responses to treatment in patients with hereditary vitamin D-resistant rickets. Horm. Res. Paediatr. 78, 326–331 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Pike, J. W. & Christakos, S. Biology and mechanisms of action of the vitamin D hormone. Endocrinol. Metab. Clin. North Am. 46, 815–843 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Pike, J. W., Meyer, M. B., Lee, S. M., Onal, M. & Benkusky, N. A. The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. J. Clin. Invest. 127, 1146–1154 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Wei, R., Dhawan, P., Baiocchi, R. A., Kim, K. Y. & Christakos, S. PU.1 and epigenetic signals modulate 1,25-dihydroxyvitamin D3 and C/EBPα regulation of the human cathelicidin antimicrobial peptide gene in lung epithelial cells. J. Cell Physiol. 234, 10345–10359 (2019).

    Article  CAS  PubMed  Google Scholar 

  156. Seth-Vollenweider, T., Joshi, S., Dhawan, P., Sif, S. & Christakos, S. Novel mechanism of negative regulation of 1,25-dihydroxyvitamin D3-induced 25-hydroxyvitamin D3 24-hydroxylase (Cyp24a1) Transcription: epigenetic modification involving cross-talk between protein-arginine methyltransferase 5 and the SWI/SNF complex. J. Biol. Chem. 289, 33958–33970 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Meyer, M. B., Benkusky, N. A. & Pike, J. W. The RUNX2 cistrome in osteoblasts: characterization, down-regulation following differentiation, and relationship to gene expression. J. Biol. Chem. 289, 16016–16031 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Pike, J. W., Meyer, M. B., St John, H. C. & Benkusky, N. A. Epigenetic histone modifications and master regulators as determinants of context dependent nuclear receptor activity in bone cells. Bone 81, 757–764 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ding, N. et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 153, 601–613 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Wei, Z. et al. Vitamin D switches BAF complexes to protect β cells. Cell 173, 1135–1149.e15 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Bikle, D. D., Nemanic, M. K., Whitney, J. O. & Elias, P. W. Neonatal human foreskin keratinocytes produce 1,25-dihydroxyvitamin D3. Biochemistry 25, 1545–1548 (1986).

    Article  CAS  PubMed  Google Scholar 

  163. Stumpf, W. E., Sar, M., Reid, F. A., Tanaka, Y. & DeLuca, H. F. Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science 206, 1188–1190 (1979).

    Article  CAS  PubMed  Google Scholar 

  164. Pillai, S., Bikle, D. D. & Elias, P. M. 1,25-Dihydroxyvitamin D production and receptor binding in human keratinocytes varies with differentiation. J. Biol. Chem. 263, 5390–5395 (1988).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  166. Smith, E. L., Walworth, N. C. & 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).

    Article  CAS  PubMed  Google Scholar 

  167. Oda, Y. et al. Vitamin D receptor and coactivators SRC2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. J. Invest. Dermatol. 129, 1367–1378 (2009).

    Article  CAS  PubMed  Google Scholar 

  168. Tu, C. L. et al. Ablation of the calcium-sensing receptor in keratinocytes impairs epidermal differentiation and barrier function. J. Invest. Dermatol. 132, 2350–2359 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Oda, Y. et al. Vitamin D receptor is required for proliferation, migration, and differentiation of epidermal stem cells and progeny during cutaneous wound repair. J. Invest. Dermatol. 138, 2423–2431 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Tu, C. L., Celli, A., Mauro, T. & Chang, W. The calcium-sensing receptor regulates epidermal intracellular Ca(2+) signaling and re-epithelialization after wounding. J. Invest. Dermatol. 139, 919–929 (2019).

    Article  CAS  PubMed  Google Scholar 

  171. Teichert, A., Elalieh, H. & Bikle, D. Disruption of the hedgehog signaling pathway contributes to the hair follicle cycling deficiency in Vdr knockout mice. J. Cell. Physiol. 225, 482–489 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Bikle, D. D., Elalieh, H., Chang, S., Xie, Z. & Sundberg, J. P. Development and progression of alopecia in the vitamin D receptor null mouse. J. Cell. Physiol. 207, 340–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  173. Li, Y. C. et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc. Natl Acad. Sci. USA 94, 9831–9835 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Palmer, H. G., Anjos-Afonso, F., Carmeliet, G., Takeda, H. & Watt, F. M. The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis. PLOS ONE 3, e1483 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kretzschmar, K. & Watt, F. M. Markers of epidermal stem cell subpopulations in adult mammalian skin. Cold Spring Harb. Perspect. Med. 4, a013631 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Eichner, R., Sun, T. T. & Aebi, U. The role of keratin subfamilies and keratin pairs in the formation of human epidermal intermediate filaments. J. Cell Biol. 102, 1767–1777 (1986).

    Article  CAS  PubMed  Google Scholar 

  177. Warhol, M. J., Roth, J., Lucocq, J. M., Pinkus, G. S. & Rice, R. H. Immuno-ultrastructural localization of involucrin in squamous epithelium and cultured keratinocytes. J. Histochem. Cytochem. 33, 141–149 (1985).

    Article  CAS  PubMed  Google Scholar 

  178. Thacher, S. M. & Rice, R. H. Keratinocyte-specific transglutaminase of cultured human epidermal cells: relation to cross-linked envelope formation and terminal differentiation. Cell 40, 685–695 (1985).

    Article  CAS  PubMed  Google Scholar 

  179. Steven, A. C., Bisher, M. E., Roop, D. R. & Steinert, P. M. Biosynthetic pathways of filaggrin and loricrin–two major proteins expressed by terminally differentiated epidermal keratinocytes. J. Struct. Biol. 104, 150–162 (1990).

    Article  CAS  PubMed  Google Scholar 

  180. Freeman, S. C. & Sonthalia, S. Histology, keratohyalin granules. StatPearls https://www.ncbi.nlm.nih.gov/books/NBK537049/ (2019).

  181. Dale, B. A., Resing, K. A. & Lonsdale-Eccles, J. D. Filaggrin: a keratin filament associated protein. Ann. NY Acad. Sci. 455, 330–342 (1985).

    Article  CAS  PubMed  Google Scholar 

  182. Levin, J., Friedlander, S. F. & Del Rosso, J. Q. Atopic dermatitis and the stratum corneum: part 2: other structural and functional characteristics of the stratum corneum barrier in atopic skin. J. Clin. Aesthet. Dermatol. 6, 49–54 (2013).

    PubMed  PubMed Central  Google Scholar 

  183. Mehrel, T. et al. Identification of a major keratinocyte cell envelope protein, loricrin. Cell 61, 1103–1112 (1990).

    Article  CAS  PubMed  Google Scholar 

  184. Menon, G. K., Lee, S. E. & Lee, S. H. An overview of epidermal lamellar bodies: novel roles in biological adaptations and secondary barriers. J. Dermatol. Sci. 92, 10–17 (2018).

    Article  CAS  PubMed  Google Scholar 

  185. Feingold, K. R. & Elias, P. M. Role of lipids in the formation and maintenance of the cutaneous permeability barrier. Biochim. Biophys. Acta 1841, 280–294 (2014).

    Article  CAS  PubMed  Google Scholar 

  186. Aberg, K. M. et al. Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers. J. Invest. Dermatol. 128, 917–925 (2008).

    Article  CAS  PubMed  Google Scholar 

  187. Bikle, D. D. & Pillai, S. Vitamin D, calcium, and epidermal differentiation. Endocr. Rev. 14, 3–19 (1993).

    CAS  PubMed  Google Scholar 

  188. Bikle, D. D., Pillai, S. & Gee, E. Squamous carcinoma cell lines produce 1,25 dihydroxyvitamin D, but fail to respond to its prodifferentiating effect. J. Invest. Dermatol. 97, 435–441 (1991).

    Article  CAS  PubMed  Google Scholar 

  189. McLane, J. A., Katz, M. & Abdelkader, N. Effect of 1,25-dihydroxyvitamin D3 on human keratinocytes grown under different culture conditions. In Vitro Cell. Dev. Biol. 26, 379–387 (1990).

    Article  CAS  PubMed  Google Scholar 

  190. Hawker, N. P., Pennypacker, S. D., Chang, S. M. & Bikle, D. D. Regulation of human epidermal keratinocyte differentiation by the vitamin D receptor and its coactivators DRIP205, SRC2, and SRC3. J. Invest. Dermatol. 127, 874–880 (2007).

    Article  CAS  PubMed  Google Scholar 

  191. Schauber, J. et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J. Clin. Invest. 117, 803–811 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Schauber, J., Dorschner, R. A., Yamasaki, K., Brouha, B. & Gallo, R. L. Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli. Immunology 118, 509–519 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Oda, Y. et al. Vitamin D receptor and coactivators SRC 2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. J. Invest. Dermatol. 129, 1367–1378 (2009).

    Article  CAS  PubMed  Google Scholar 

  194. Muehleisen, B. et al. PTH/PTHrP and vitamin D control antimicrobial peptide expression and susceptibility to bacterial skin infection. Sci. Transl Med. 4, 135ra66 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Zehnder, D. et al. Extrarenal expression of 25-hydroxyvitamin D3-1α-hydroxylase. J. Clin. Endocrinol. Metab. 86, 888–894 (2001).

    CAS  PubMed  Google Scholar 

  196. Stumpf, W. E., Clark, S. A., Sar, M. & DeLuca, H. F. Topographical and developmental studies on target sites of 1,25 (OH)2 vitamin D3 in skin. Cell Tissue Res. 238, 489–496 (1984).

    Article  CAS  PubMed  Google Scholar 

  197. Oda, Y. et al. Two distinct coactivators, DRIP/mediator and SRC/p160, are differentially involved in vitamin D receptor transactivation during keratinocyte differentiation. Mol. Endocrinol. 17, 2329–2339 (2003).

    Article  CAS  PubMed  Google Scholar 

  198. Oda, Y., Ishikawa, M. H., Hawker, N. P., Yun, Q. C. & Bikle, D. D. Differential role of two VDR coactivators, DRIP205 and SRC-3, in keratinocyte proliferation and differentiation. J. Steroid Biochem. Mol. Biol. 103, 776–780 (2007).

    Article  CAS  PubMed  Google Scholar 

  199. Oda, Y. et al. Coactivator MED1 ablation in keratinocytes results in hair-cycling defects and epidermal alterations. J. Invest. Dermatol. 132, 1075–1083 (2012).

    Article  CAS  PubMed  Google Scholar 

  200. Schauber, J. et al. Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3. J. Invest. Dermatol. 128, 816–824 (2008).

    Article  CAS  PubMed  Google Scholar 

  201. Bikle, D. D., Xie, Z. & Tu, C. L. Calcium regulation of keratinocyte differentiation. Expert. Rev. Endocrinol. Metab. 7, 461–472 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Tu, C. L., Chang, W. & Bikle, D. D. The extracellular calcium-sensing receptor is required for calcium-induced differentiation in human keratinocytes. J. Biol. Chem. 276, 41079–41085 (2001).

    Article  CAS  PubMed  Google Scholar 

  203. Tu, C. L., Chang, W. & Bikle, D. D. Phospholipase Cγ1 is required for activation of store-operated channels in human keratinocytes. J. Invest. Dermatol. 124, 187–197 (2005).

    Article  CAS  PubMed  Google Scholar 

  204. Tu, C., Chang, W., Xie, Z. & Bikle, D. Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes. J. Biol. Chem. 283, 3519–3528 (2008).

    Article  CAS  PubMed  Google Scholar 

  205. Xie, Z., Singleton, P. A., Bourguignon, L. Y. & Bikle, D. D. Calcium-induced human keratinocyte differentiation requires src- and fyn-mediated phosphatidylinositol 3-kinase-dependent activation of phospholipase C-γ1. Mol. Biol. Cell 16, 3236–3246 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Xie, Z. & Bikle, D. D. The recruitment of phosphatidylinositol 3-kinase to the E-cadherin-catenin complex at the plasma membrane is required for calcium-induced phospholipase C-γ1 activation and human keratinocyte differentiation. J. Biol. Chem. 282, 8695–8703 (2007).

    Article  CAS  PubMed  Google Scholar 

  207. Xie, Z., Chang, S. M., Pennypacker, S. D., Liao, E. Y. & Bikle, D. D. Phosphatidylinositol-4-phosphate 5-kinase 1α mediates extracellular calcium-induced keratinocyte differentiation. Mol. Biol. Cell 20, 1695–1704 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Tu, C. L., Oda, Y., Komuves, L. & Bikle, D. D. The role of the calcium-sensing receptor in epidermal differentiation. Cell Calcium 35, 265–273 (2004).

    Article  CAS  PubMed  Google Scholar 

  209. Tu, C. L., Chang, W. & Bikle, D. D. The role of the calcium sensing receptor in regulating intracellular calcium handling in human epidermal keratinocytes. J. Invest. Dermatol. 127, 1074–1083 (2007).

    Article  CAS  PubMed  Google Scholar 

  210. Canaff, L. & Hendy, G. N. Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J. Biol. Chem. 277, 30337–30350 (2002).

    Article  CAS  PubMed  Google Scholar 

  211. Xie, Z. & Bikle, D. D. Cloning of the human phospholipase C-γ1 promoter and identification of a DR6-type vitamin D-responsive element. J. Biol. Chem. 272, 6573–6577 (1997).

    Article  CAS  PubMed  Google Scholar 

  212. Su, M. J., Bikle, D. D., Mancianti, M. L. & Pillai, S. 1,25-Dihydroxyvitamin D3 potentiates the keratinocyte response to calcium. J. Biol. Chem. 269, 14723–14729 (1994).

    CAS  PubMed  Google Scholar 

  213. Gniadecki, R., Gajkowska, B. & Hansen, M. 1,25-Dihydroxyvitamin D3 stimulates the assembly of adherens junctions in keratinocytes: involvement of protein kinase C. Endocrinology 138, 2241–2248 (1997).

    Article  CAS  PubMed  Google Scholar 

  214. Hu, L., Bikle, D. D. & Oda, Y. Reciprocal role of vitamin D receptor on β-catenin regulated keratinocyte proliferation and differentiation. J. Steroid Biochem. Mol. Biol. 144, 237–241 (2014).

    Article  CAS  PubMed  Google Scholar 

  215. Xie, Z. et al. Lack of the vitamin D receptor is associated with reduced epidermal differentiation and hair follicle growth. J. Invest. Dermatol. 118, 11–16 (2002).

    Article  CAS  PubMed  Google Scholar 

  216. Watt, F. M. & Collins, C. A. Role of β-catenin in epidermal stem cell expansion, lineage selection, and cancer. Cold Spring Harb. Symp. Quant. Biol. 73, 503–512 (2008).

    Article  CAS  PubMed  Google Scholar 

  217. Luderer, H. F., Gori, F. & Demay, M. B. Lymphoid enhancer-binding factor-1 (LEF1) interacts with the DNA-binding domain of the vitamin D receptor. J. Biol. Chem. 286, 18444–18451 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Hill, N. T. et al. 1α, 25-Dihydroxyvitamin D(3) and the vitamin D receptor regulates ΔNp63α levels and keratinocyte proliferation. Cell Death Dis. 6, e1781 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Stambolsky, P. et al. Modulation of the vitamin D3 response by cancer-associated mutant p53. Cancer Cell 17, 273–285 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Salehi-Tabar, R. et al. Vitamin D receptor as a master regulator of the c-MYC/MXD1 network. Proc. Natl Acad. Sci. USA 109, 18827–18832 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  221. Reichrath, J., Saternus, R. & Vogt, T. Endocrine actions of vitamin D in skin: relevance for photocarcinogenesis of non-melanoma skin cancer, and beyond. Mol. Cell. Endocrinol. 453, 96–102 (2017).

    Article  CAS  PubMed  Google Scholar 

  222. Stenn, K. S. & Paus, R. Controls of hair follicle cycling. Physiol. Rev. 81, 449–494 (2001).

    Article  CAS  PubMed  Google Scholar 

  223. Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nat. Biotechnol. 22, 411–417 (2004).

    Article  CAS  PubMed  Google Scholar 

  224. Schneider, M. R., Schmidt-Ullrich, R. & Paus, R. The hair follicle as a dynamic miniorgan. Curr. Biol. 19, R132–R142 (2009).

    Article  CAS  PubMed  Google Scholar 

  225. Gonzales, K. A. U. & Fuchs, E. Skin and its regenerative powers: an alliance between stem cells and their niche. Dev. Cell 43, 387–401 (2017).

    Article  CAS  PubMed  Google Scholar 

  226. Hochberg, Z. et al. Calcitriol-resistant rickets with alopecia. Arch. Dermatol. 121, 646–647 (1985).

    Article  CAS  PubMed  Google Scholar 

  227. Marx, S. J., Bliziotes, M. M. & Nanes, M. Analysis of the relation between alopecia and resistance to 1,25-dihydroxyvitamin D. Clin. Endocrinol. 25, 373–381 (1986).

    Article  CAS  Google Scholar 

  228. Sakai, Y. & Demay, M. B. Evaluation of keratinocyte proliferation and differentiation in vitamin D receptor knockout mice. Endocrinology 141, 2043–2049 (2000).

    Article  CAS  PubMed  Google Scholar 

  229. Teichert, A. E., Elalieh, H., Elias, P. M., Welsh, J. & Bikle, D. D. Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice. J. Invest. Dermatol. 131, 2289–2297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Panteleyev, A. A., Botchkareva, N. V., Sundberg, J. P., Christiano, A. M. & Paus, R. The role of the hairless (hr) gene in the regulation of hair follicle catagen transformation. Am. J. Pathol. 155, 159–171 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Miller, J. et al. Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene. J. Invest. Dermatol. 117, 612–617 (2001).

    Article  CAS  PubMed  Google Scholar 

  232. Ahmad, W. et al. Alopecia universalis associated with a mutation in the human hairless gene. Science 279, 720–724 (1998).

    Article  CAS  PubMed  Google Scholar 

  233. Millar, S. E. Molecular mechanisms regulating hair follicle development. J. Invest. Dermatol. 118, 216–225 (2002).

    Article  CAS  PubMed  Google Scholar 

  234. Xie, Z., Chang, S., Oda, Y. & Bikle, D. D. Hairless suppresses vitamin D receptor transactivation in human keratinocytes. Endocrinology 147, 314–323 (2006).

    Article  CAS  PubMed  Google Scholar 

  235. Hsieh, J. C. et al. Analysis of hairless corepressor mutants to characterize molecular cooperation with the vitamin D receptor in promoting the mammalian hair cycle. J. Cell. Biochem. 110, 671–686 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Hsieh, J. C. et al. Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. J. Biol. Chem. 278, 38665–38674 (2003).

    Article  CAS  PubMed  Google Scholar 

  237. Cianferotti, L., Cox, M., Skorija, K. & Demay, M. B. Vitamin D receptor is essential for normal keratinocyte stem cell function. Proc. Natl Acad. Sci. USA 104, 9428–9433 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  239. Lisse, T. S. et al. The vitamin D receptor is required for activation of cWnt and hedgehog signaling in keratinocytes. Mol. Endocrinol. 28, 1698–1706 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Teichert, A., Elalieh, H., Elias, P., Welsh, J. & Bikle, D. Over-expression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor null mice. J. Invest. Dermatol. 131, 2289–2297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Zarach, J. M., Beaudoin, G. M. 3rd, Coulombe, P. A. & Thompson, C. C. The co-repressor hairless has a role in epithelial cell differentiation in the skin. Development 131, 4189–4200 (2004).

    Article  CAS  PubMed  Google Scholar 

  242. DasGupta, R., Rhee, H. & Fuchs, E. A developmental conundrum: a stabilized form of β-catenin lacking the transcriptional activation domain triggers features of hair cell fate in epidermal cells and epidermal cell fate in hair follicle cells. J. Cell Biol. 158, 331–344 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Daroach, M., Narang, T., Saikia, U. N., Sachdeva, N. & Sendhil Kumaran, M. Correlation of vitamin D and vitamin D receptor expression in patients with alopecia areata: a clinical paradigm. Int. J. Dermatol. 57, 217–222 (2018).

    Article  CAS  PubMed  Google Scholar 

  244. Lee, S., Kim, B. J., Lee, C. H. & Lee, W. S. Increased prevalence of vitamin D deficiency in patients with alopecia areata: a systematic review and meta-analysis. J. Eur. Acad. Dermatol. Venereol. 32, 1214–1221 (2018).

    Article  CAS  PubMed  Google Scholar 

  245. Umar, M. et al. Vitamin D and the pathophysiology of inflammatory skin diseases. Skin Pharmacol. Physiol. 31, 74–86 (2018).

    Article  CAS  PubMed  Google Scholar 

  246. Mady, L. J. et al. The transient role for calcium and vitamin D during the developmental hair follicle cycle. J. Invest. Dermatol. 136, 1337–1345 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Greenlee, R. T., Hill-Harmon, M. B., Murray, T. & Thun, M. Cancer statistics, 2001. CA Cancer J. Clin. 51, 15–36 (2001).

    Article  CAS  PubMed  Google Scholar 

  248. Reichrath, J. et al. Analysis of 1,25-dihydroxyvitamin D(3) receptors (VDR) in basal cell carcinomas. Am. J. Pathol. 155, 583–589 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Reichrath, J. et al. Analysis of the vitamin D system in cutaneous squamous cell carcinomas. J. Cutan. Pathol. 31, 224–231 (2004).

    Article  PubMed  Google Scholar 

  250. Ratnam, A. V., Bikle, D. D., Su, M. J. & Pillai, S. Squamous carcinoma cell lines fail to respond to 1,25-dihydroxyvitamin D despite normal levels of the vitamin D receptor. J. Invest. Dermatol. 106, 522–525 (1996).

    Article  CAS  PubMed  Google Scholar 

  251. Rheinwald, J. G. & Beckett, M. A. Defective terminal differentiation in culture as a consistent and selectable character of malignant human keratinocytes. Cell 22, 629–632 (1980).

    Article  CAS  PubMed  Google Scholar 

  252. Xie, Z. et al. Phospholipase C-γ1 is required for the epidermal growth factor receptor-induced squamous cell carcinoma cell mitogenesis. Biochem. Biophys. Res. Commun. 397, 296–300 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Zinser, G. M., Sundberg, J. P. & Welsh, J. Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis. Carcinogenesis 23, 2103–2109 (2002).

    Article  CAS  PubMed  Google Scholar 

  254. Ellison, T. I., Smith, M. K., Gilliam, A. C. & Macdonald, P. N. Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis. J. Invest. Dermatol. 128, 2508–2517 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Bikle, D. D., Oda, Y., Tu, C. L. & Jiang, Y. Novel mechanisms for the vitamin D receptor (VDR) in the skin and in skin cancer. J. Steroid Biochem. Mol. Biol. 148, 47–51 (2015).

    Article  CAS  PubMed  Google Scholar 

  256. Tang, J. Y. et al. Vitamin D in cutaneous carcinogenesis: part I. J. Am. Acad. Dermatol. 67, 803.e1–803.e12 (2012).

    Article  CAS  Google Scholar 

  257. Tang, J. Y. et al. Vitamin D in cutaneous carcinogenesis: part II. J. Am. Acad. Dermatol. 67, 817.e1–817.e11 (2012).

    Article  CAS  Google Scholar 

  258. Bikle, D. D., Jiang, Y., Nguyen, T., Oda, Y. & Tu, C. L. Disruption of vitamin D and calcium signaling in keratinocytes predisposes to skin cancer. Front. Physiol. 7, 296 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  259. Hussein, M. R. Ultraviolet radiation and skin cancer: molecular mechanisms. J. Cutan. Pathol. 32, 191–205 (2005).

    Article  PubMed  Google Scholar 

  260. Chen, R. H., Maher, V. M. & McCormick, J. J. Effect of excision repair by diploid human fibroblasts on the kinds and locations of mutations induced by (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene in the coding region of the HPRT gene. Proc. Natl Acad. Sci. USA 87, 8680–8684 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Wood, R. D. DNA damage recognition during nucleotide excision repair in mammalian cells. Biochimie 81, 39–44 (1999).

    Article  CAS  PubMed  Google Scholar 

  262. Demetriou, S. K. et al. Vitamin D receptor mediates DNA repair and is UV inducible in intact epidermis but not in cultured keratinocytes. J. Invest. Dermatol. 132, 2097–2100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Gupta, R. et al. Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products. J. Invest. Dermatol. 127, 707–715 (2007).

    Article  CAS  PubMed  Google Scholar 

  264. Moll, P. R., Sander, V., Frischauf, A. M. & Richter, K. Expression profiling of vitamin D treated primary human keratinocytes. J. Cell. Biochem. 100, 574–592 (2007).

    Article  CAS  PubMed  Google Scholar 

  265. Ping, X. L. et al. PTCH mutations in squamous cell carcinoma of the skin. J. Invest. Dermatol. 116, 614–616 (2001).

    Article  CAS  PubMed  Google Scholar 

  266. Aszterbaum, M. et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J. Invest. Dermatol. 110, 885–888 (1998).

    Article  CAS  PubMed  Google Scholar 

  267. Hahn, H. et al. Mutations of the human homolog of DROSOPHILA patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

    Article  CAS  PubMed  Google Scholar 

  268. Regl, G. et al. The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells. Oncogene 23, 1263–1274 (2004).

    Article  CAS  PubMed  Google Scholar 

  269. Regl, G. et al. Human GLI2 and GLI1 are part of a positive feedback mechanism in basal cell carcinoma. Oncogene 21, 5529–5539 (2002).

    Article  CAS  PubMed  Google Scholar 

  270. Grachtchouk, M. et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat. Genet. 24, 216–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  271. Chan, E. F., Gat, U., McNiff, J. M. & Fuchs, E. A common human skin tumour is caused by activating mutations in β-catenin. Nat. Genet. 21, 410–413 (1999).

    Article  CAS  PubMed  Google Scholar 

  272. Mercer, T. R., Dinger, M. E. & Mattick, J. S. Long non-coding RNAs: insights into functions. Nat. Rev. Genet. 10, 155–159 (2009).

    Article  CAS  PubMed  Google Scholar 

  273. Mattick, J. S. Long noncoding RNAs in cell and developmental biology. Semin. Cell Dev. Biol. 22, 327 (2011).

    Article  PubMed  Google Scholar 

  274. Jiang, Y. J. & Bikle, D. D. LncRNA: a new player in 1α, 25(OH)(2) vitamin D(3) /VDR protection against skin cancer formation. Exp. Dermatol. 23, 147–150 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Underhill, C. CD44: the hyaluronan receptor. J. Cell Sci. 103, 293–298 (1992).

    CAS  PubMed  Google Scholar 

  276. Screaton, G. R. et al. Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc. Natl Acad. Sci. USA 89, 12160–12164 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Haggerty, J. G., Bretton, R. H. & Milstone, L. M. Identification and characterization of a cell surface proteoglycan on keratinocytes. J. Invest. Dermatol. 99, 374–380 (1992).

    Article  CAS  PubMed  Google Scholar 

  278. Averbeck, M. et al. Differential regulation of hyaluronan metabolism in the epidermal and dermal compartments of human skin by UVB irradiation. J. Invest. Dermatol. 127, 687–697 (2007).

    Article  CAS  PubMed  Google Scholar 

  279. Stern, R. Complicated hyaluronan patterns in skin: enlightenment by UVB? J. Invest. Dermatol. 127, 512–513 (2007).

    Article  CAS  PubMed  Google Scholar 

  280. Bourguignon, L. Y. et al. Selective matrix (hyaluronan) interaction with CD44 and RhoGTPase signaling promotes keratinocyte functions and overcomes age-related epidermal dysfunction. J. Dermatol. Sci. 72, 32–44 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Bourguignon, L. Y. & Bikle, D. Selective hyaluronan–CD44 signaling promotes miRNA-21 expression and interacts with vitamin D function during cutaneous squamous cell carcinomas progression following UV irradiation. Front. Immunol. 6, 224 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Hsu, J. Y., Feldman, D., McNeal, J. E. & Peehl, D. M. Reduced 1α-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res. 61, 2852–2856 (2001).

    CAS  PubMed  Google Scholar 

  283. Brożyna, A. A., Jóźwicki, W., Janjetovic, Z. & Slominski, A. T. Expression of the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1) decreases during melanoma progression. Hum. Pathol. 44, 374–387 (2013).

    Article  CAS  PubMed  Google Scholar 

  284. Anderson, M. G., Nakane, M., Ruan, X., Kroeger, P. E. & Wu-Wong, J. R. Expression of VDR and CYP24A1 mRNA in human tumors. Cancer Chemother. Pharmacol. 57, 234–240 (2006).

    Article  CAS  PubMed  Google Scholar 

  285. Solomon, C., White, J. H. & Kremer, R. Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor α. J. Clin. Invest. 103, 1729–1735 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Larriba, M. J. et al. Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis 30, 1459–1468 (2009).

    Article  CAS  PubMed  Google Scholar 

  287. Mittal, M. K., Myers, J. N., Misra, S., Bailey, C. K. & Chaudhuri, G. In vivo binding to and functional repression of the VDR gene promoter by SLUG in human breast cells. Biochem. Biophys. Res. Commun. 372, 30–34 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Marik, R. et al. DNA methylation-related vitamin D receptor insensitivity in breast cancer. Cancer Biol. Ther. 10, 44–53 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Mohri, T., Nakajima, M., Takagi, S., Komagata, S. & Yokoi, T. MicroRNA regulates human vitamin D receptor. Int. J. Cancer 125, 1328–1333 (2009).

    Article  CAS  PubMed  Google Scholar 

  290. Reichrath, J., Reichrath, S., Heyne, K., Vogt, T. & Roemer, K. Tumor suppression in skin and other tissues via cross-talk between vitamin D- and p53-signaling. Front. Physiol. 5, 166 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  291. Sequeira, V. B. et al. The role of the vitamin D receptor and ERp57 in photoprotection by 1α,25-dihydroxyvitamin D3. Mol. Endocrinol. 26, 574–582 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Chen, H. et al. Vitamin D directly regulates Mdm2 gene expression in osteoblasts. Biochem. Biophys. Res. Commun. 430, 370–374 (2013).

    Article  CAS  PubMed  Google Scholar 

  293. Heyne, K., Heil, T. C., Bette, B., Reichrath, J. & Roemer, K. MDM2 binds and inhibits vitamin D receptor. Cell Cycle 14, 2003–2010 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Dixon, K. M. et al. 1α,25(OH)(2)-vitamin D and a nongenomic vitamin D analogue inhibit ultraviolet radiation-induced skin carcinogenesis. Cancer Prev. Res. 4, 1485–1494 (2011).

    Article  CAS  Google Scholar 

  295. Skrajnowska, D. & Bobrowska-Korczak, B. Potential molecular mechanisms of the anti-cancer activity of vitamin D. Anticancer Res. 39, 3353–3363 (2019).

    Article  PubMed  Google Scholar 

  296. Plikus, M. V. et al. Epithelial stem cells and implications for wound repair. Semin. Cell Dev. Biol. 23, 946–953 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Oda, Y. et al. Combined deletion of the vitamin D receptor and calcium-sensing receptor delays wound re-epithelialization. Endocrinology 158, 1929–1938 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Palmer, H. G., Martinez, D., Carmeliet, G. & Watt, F. M. The vitamin D receptor is required for mouse hair cycle progression but not for maintenance of the epidermal stem cell compartment. J. Invest. Dermatol. 128, 2113–2117 (2008).

    Article  CAS  PubMed  Google Scholar 

  299. Luderer, H. F., Nazarian, R. M., Zhu, E. D. & Demay, M. B. Ligand-dependent actions of the vitamin D receptor are required for activation of TGF-β signaling during the inflammatory response to cutaneous injury. Endocrinology 154, 16–24 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medicine and Dermatology, University of California San Francisco, San Francisco, CA, USA

    Daniel Bikle

  2. VA Medical Center, San Francisco, CA, USA

    Daniel Bikle

  3. Departments of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, the State University of New Jersey, Newark, NJ, USA

    Sylvia Christakos

Authors
  1. Daniel Bikle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylvia Christakos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Daniel Bikle.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks M. Holick, G. Jones, M. Hewison and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Cerebrotendinous xanthomatosis

The disease that results from inactivating mutations in CYP27A1. Cerebrotendinous xanthomatosis manifests as a reduction in bile and cholesterol metabolism.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bikle, D., Christakos, S. New aspects of vitamin D metabolism and action — addressing the skin as source and target. Nat Rev Endocrinol 16, 234–252 (2020). https://doi.org/10.1038/s41574-019-0312-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-019-0312-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing