Archives of Dermatological Research

, Volume 282, Issue 3, pp 164–167 | Cite as

Calcipotriol (MC 903), a novel vitamin D3 analogue stimulates terminal differentiation and inhibits proliferation of cultured human keratinocytes

  • K. Kragballe
  • I. L. Wildfang
Original Contributions


The hormonally active form of vitamin D3, 1,25-dihydroxy vitamin D3 [1,25-(OH)2-D3; calcitriol], regulates the differentiation and proliferation of epidermal keratinocytes in vitro. MC 903 (calcipotriol) is a novel vitamin D3 analogue which is at least 100 times less potent than 1,25-(OH)2-D3 in its effects on calcium homeostasis. The present study compared the effects of MC 903 and 1,25-(OH)2-D3 on terminal differentiation and proliferation of cultured normal human keratinocytes. Keratinocytes were grown in McCoy's 5A medium supplemented with penicillin (50 IU/ml), streptomycin (50 Μg/ml), l-serine (4×10−4M), and 10% human type AB serum. MC 903, 1,25-(OH)2-D3 or 1α-OH-D3 (10−12M−10−8M) was added with each feeding when cultures became preconfluent. After incubation for 24 h with D3 vitamins, cultures were extracted for transglutaminase, and the enzyme activity was indexed against DNA content. The activity of transglutaminase, the enzyme reponsible for cross-linking the proteins of the cornified envelope, was maximally stimulated by 388% with MC 903 (10−8M), by 328% with 1,25-(OH)2-D3 (10−8M), and by 27% with 1α-OH-D3 (10−8M) compared with vehicle. After incubation for 2 weeks the number of keratinocytes with cornified envelopes had increased by 288% with MC 903 (10−8M), by 360% with 1,25-(OH)2-D3 (10−8M), and by 149% with 1α-OH-D3 (10−8M) compared with vehicle. Simultaneously the incorporation of (3H)thymidine into DNA was decreased by 64% with MC 903 (10−8M), by 71% with 1,25-(OH)2-D3 (10−8M), and by 10% with 1α-OH-D3 (10−8M). There was a corresponding decrease in cell number. These results demonstrate that both MC 903 and 1,25-(OH)2-D3 are potent modulators of keratinocytes differentiation and proliferation in vitro. Because MC 903 is much less active than 1,25-(OH)2-D3 in causing hypercalcemia, this compound is a candidate for the treatment of skin diseases characterized by aberrant epidermal differentiation and proliferation.

Key words

Vitamin D3 analogues Keratinocyte culture Differentiation Proliferation 


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  1. 1.
    Binderup L, Bramm E (1988) Effect of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 37:889–895Google Scholar
  2. 2.
    Calverley MJ (1987) Synthesis of MC 903 a biologically active vitamin D analogue. Tetrahedron 43:4609–4619Google Scholar
  3. 3.
    Haussler MR, Donaldson CA, Kelly MA (1985) Functions and mechanism of action of the 1,25-dihydroxy-vitamin D3 receptor. In: Norman AW, Schaefer K, Grigoleit H-G (eds) Vitamin D: a chemical, biochemical and clinical update. de Gruyter, Berlin pp 83–92Google Scholar
  4. 4.
    Hennings H, Michael D, Cheng C, Steinert P, Holbrook K, Yupar SH (1980) Calcium regulation of growth and differentiation of mouse epidermal cells in culture. Cell 245–254Google Scholar
  5. 5.
    Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T (1983) Regulation of terminal differentiation of cultured mouse epidermal cells by 1,25-dihydroxyvitamin D3. Endocrinology 113:1950–1957Google Scholar
  6. 6.
    Iukushima M, Suzuki Y, Toira Y, Matsunaga I, Ochi K, Nagano H, Nishi Y, Suda T (1975) Metabolism of 1-hydroxy vitamin D3 to 1,25-dihydroxy vitamin D3 in perfused rat liver. Biochem Biophys Res Commun 66:632–624Google Scholar
  7. 7.
    Kragballe K (1989) Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol (MC 903). Arch Dermatol 125:1647–1652Google Scholar
  8. 8.
    Kragballe K, Desjarlais L, Marcelo CL (1985) Increased DNA synthesis of uninvolved psoriatic epidermis is maintained in vitro. Br J Dermatol 112:263–270Google Scholar
  9. 9.
    Kragballe K, Bech HI, SØgaard H (1988) Improvement of psoriasis by a topical vitamin D3 analogue (MC 903) in a doubleblind study. Br J Dermatol 119:223–230Google Scholar
  10. 10.
    Liu S-C, Karasek M (1987) Isolation and growth of adult human epidermal keratinocytes. J Invest Dermatol 71:157–162Google Scholar
  11. 11.
    Marcelo CL, Kim YG, Kaine JL, Voorhees JJ (1978) Stratification, specialization, and proliferation of primary keratinocyte cultures. J Cell Biol 79:356–370Google Scholar
  12. 12.
    McLane JA, Katz M (1988) Differential effects of 1,25-dihydroxy vitamin D3 on proliferation and biochemical differentiation of cultured human epidermal keratinocytes grown in different media. Ann NY Acad Sci 548:341–343Google Scholar
  13. 13.
    Morimoto S, Yoshikawa K, Kozuka T, Kitanoy Innanaka S, Fukuo K, Koh E, Kumahara Y (1986) An open study of vitamin D3 treatment in psoriasis vulgaris. Br J Dermatol 115:421–429Google Scholar
  14. 14.
    Pillai S, Bikle DD, Eilias PM (1988) 1,25-Dihydroxy vitamin D production and receptor binding in human keratinocytes correlates with differentiation. J Biol Chem 263:5390–5395Google Scholar
  15. 15.
    Simpson RU, DeLuca HF (1980) Characterization of a receptor like protein for 1,25 dihydroxyvitamin D in rat skin. Proc Natl Acad Sci USA 77:5822–5827Google Scholar
  16. 16.
    Smith EL, Walworth NC, Holick MF (1986) Effect of 1,25-dihydroxyvitamin D3 on the morphologic and epidermal keratinocytes grown in serum free conditions. J Invest Dermatol 86:709–714Google Scholar
  17. 17.
    Smith EL, Pincus SH, Konovan L, Holick MF (1988) A novel approach for the evaluation and treatment of psoriasis. Oral or topical use of 1,25-dihydroxyvitamin D3 can be safe and effective therapy of psoriasis. J Am Acad Dermatol 19:516–528Google Scholar
  18. 18.
    Yuspa SH, Ben T, Hennings H, Lichti U (1980) Phorbol ester tumor promotors induce epidermal transglutaminase activity. Biochem Biophys Res Commun 97:700–708Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • K. Kragballe
    • 1
  • I. L. Wildfang
    • 1
  1. 1.Department of DermatologyMarselisborg Hospital, University of AarhusAarhus CDenmark

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