Stimulation versus inhibition of keratinocyte growth by 1,25-Dihydroxyvitamin D3: dependence on cell culture conditions.

1,25-Dihydroxyvitamin D3 (1,25[OH]2D3) inhibits proliferation of keratinocytes in vitro and psoriatic epidermal cells in vivo and is considered to be a negative regulator of keratinocyte growth. It has been recently observed, however, that 1,25(OH)2D3 and its active analogs stimulate epidermal proliferation after topical application in mice. In this study we show that 1,25(OH)2D3, depending on the culture conditions, can either stimulate or inhibit DNA synthesis in human keratinocytes. In cells cultured with 0.15 mM calcium in the absence or with low levels (0.1 ng/ml) of epidermal growth factor, exposure to 10(-11) - 10(-6) M 1,25(OH)2D3 imposed cell cycle block in the late G1 phase. When keratinocytes were cultured in the presence of high extracellular calcium concentration (1.8 mM), 1,25(OH)2D3 in concentrations of 10(-11) - 10(-9) M stimulated cell growth by increasing the proportion of cells entering S phase. 1,25(OH)2D3 also stimulated growth of keratinocytes cultured in low calcium concentrations when the cells were previously suspended for a short time in a semisolid medium. Growth stimulation was absent in the presence of the anti-E-cadherin antibody, which is known to inhibit calcium-dependent differentiation. These results suggest that keratinocytes committed to terminal differentiation by an elevation of calcium concentration or suspension in a semisolid medium respond to 1,25(OH)2D3 with an increase in DNA synthesis. In contrast, proliferating undifferentiated keratinocytes may be the main target for the anti-proliferative activity of 1,25(OH)2D3.

[1]  R. Gniadecki,et al.  Stimulation of epidermal proliferation in mice with 1α,25-dihydroxyvitamin D3 and receptor-active 20-epi analogues of 1α,25-dihydroxyvitamin D3 , 1995 .

[2]  F. Watt,et al.  Stem cell patterning and fate in human epidermis , 1995, Cell.

[3]  R. Gniadecki,et al.  Inhibition of glucocorticoid‐induced epidermal and dermal atrophy with KH 1060 – a potent 20‐epi analogue of 1,25‐dihydroxyvitamin D3 , 1994, British journal of pharmacology.

[4]  W. Gulliver,et al.  Effects of 1,25 Dihydroxyvitamin D3 and Calcium on Growth and Differentiation and on c-fos and p53 Gene Expression in Normal Human Keratinocytes , 1994 .

[5]  C. Harmon,et al.  Biphasic effect of 1,25-dihydroxyvitamin D3 on human hair follicle growth and hair fiber production in whole-organ cultures. , 1994, The Journal of investigative dermatology.

[6]  H. Green,et al.  Association of basonuclin with ability of keratinocytes to multiply and with absence of terminal differentiation , 1994, The Journal of cell biology.

[7]  P. Jensen,et al.  Cadherin function is required for human keratinocytes to assemble desmosomes and stratify in response to calcium. , 1994, The Journal of investigative dermatology.

[8]  K. Hodivala,et al.  Evidence that cadherins play a role in the downregulation of integrin expression that occurs during keratinocyte terminal differentiation , 1994, The Journal of cell biology.

[9]  B. H. Davis,et al.  1,25-Dihydroxyvitamin D3 activates Raf kinase and Raf perinuclear translocation via a protein kinase C-dependent pathway. , 1993, The Journal of biological chemistry.

[10]  W. Pledger,et al.  Commitment to differentiation and expression of early differentiation markers in murine keratinocytes in vitro are regulated independently of extracellular calcium concentrations , 1993, The Journal of cell biology.

[11]  J. Voorhees,et al.  Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis , 1993, The Journal of experimental medicine.

[12]  F. Watt,et al.  Regulation of keratinocyte terminal differentiation by integrin-extracellular matrix interactions. , 1993, Journal of cell science.

[13]  M. Pittelkow,et al.  Efficacy of vitamin D3 derivatives in the treatment of psoriasis vulgaris: a preliminary report. , 1993, Mayo Clinic proceedings.

[14]  O. Clausen,et al.  1,25‐dihydroxyvitamin D3 and the vitamin D analogue KH1060 induce hyperproliferation in normal mouse epidermis , 1993, Experimental dermatology.

[15]  P. Kerkhof,et al.  Topical treatment of psoriatic plaques with 1,25‐dihydroxyvitamin D3: a cell biological study , 1993, The British journal of dermatology.

[16]  Fiona M. Watt,et al.  Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression , 1993, Cell.

[17]  M. Mol,et al.  Topical calcitriol in the treatment of chronic plaque psoriasis: a double‐blind study , 1993, The British journal of dermatology.

[18]  D. Bikle,et al.  Vitamin D, calcium, and epidermal differentiation. , 1993, Endocrine reviews.

[19]  L. Dubertret,et al.  Efficacy and safety of calcipotriol (MC 903) ointment in psoriasis vulgaris. A randomized, double-blind, right/left comparative, vehicle-controlled study. , 1992, Journal of the American Academy of Dermatology.

[20]  M. Walters.  Newly identified actions of the vitamin D endocrine system. , 1992, Endocrine reviews.

[21]  P. Jensen,et al.  Regulation of keratinocyte intercellular junction organization and epidermal morphogenesis by E-cadherin , 1992, The Journal of cell biology.

[22]  L. Nanney,et al.  Epidermal Growth Factor and Related Growth Factors , 1991, International journal of dermatology.

[23]  M. Haussler,et al.  Expression of 1,25-dihydroxyvitamin D3 receptors in normal and psoriatic skin. , 1991, The Journal of investigative dermatology.

[24]  R. Burgeson,et al.  Kalinin: an epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments , 1991, The Journal of cell biology.

[25]  R. Morris,et al.  1,25-dihydroxyvitamin D3 modulates growth of vascular smooth muscle cells. , 1991, The Journal of clinical investigation.

[26]  F. Watt,et al.  Mitogens induce calcium transients in both dividing and terminally differentiating keratinocytes. , 1991, Journal of cell science.

[27]  D. Bikle,et al.  Role of intracellular‐free calcium in the cornified envelope formation of keratinocytes: Differences in the mode of action of extracellular calcium and 1,25 dihydroxyvitamin D3 , 1991, Journal of cellular physiology.

[28]  Josephine C. Adams,et al.  Changes in keratinocyte adhesion during terminal differentiation: Reduction in fibronectin binding precedes α 5 β 1 integrin loss from the cell surface , 1990, Cell.

[29]  T. Sun,et al.  Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis , 1990, Cell.

[30]  Josephine C. Adams,et al.  Fibronectin inhibits the terminal differentiation of human keratinocytes , 1989, Nature.

[31]  M. Katz,et al.  Differential Effects of 1,25‐Dihydroxy‐vitamin D3 on Proliferation and Biochemical Differentiation of Cultured Human Epidermal Keratinocytes Grown in Different Media , 1988 .

[32]  F. Watt,et al.  A model for in vitro studies of epidermal homeostasis: proliferation and involucrin synthesis by cultured human keratinocytes during recovery after stripping off the suprabasal layers. , 1988, The Journal of investigative dermatology.

[33]  P. Elias,et al.  1,25-Dihydroxyvitamin D production and receptor binding in human keratinocytes varies with differentiation. , 1988, The Journal of biological chemistry.

[34]  C. Potten,et al.  Epithelial stem cells in vivo , 1988, Journal of Cell Science.

[35]  M. Holick,et al.  Skin as the site of vitamin D synthesis and target tissue for 1,25-dihydroxyvitamin D3. Use of calcitriol (1,25-dihydroxyvitamin D3) for treatment of psoriasis. , 1987, Archives of dermatology.

[36]  F. Watt.  Influence of Cell Shape and Adhesiveness on Stratification and Terminal Differentiation of Human Keratinocytes in Culture , 1987, Journal of Cell Science.

[37]  N. Walworth,et al.  Effect of 1α,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions , 1986 .

[38]  T. Kuroki,et al.  Regulation of Terminal Differentiation of Cultured Mouse Epidermal Cells by lα,25-Dihydroxyvitamin D3 , 1983 .

[39]  Karen Holbrook,et al.  Calcium regulation of growth and differentiation of mouse epidermal cells in culture , 1980, Cell.

[40]  H. DeLuca,et al.  Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. , 1979, Science.

[41]  H. Shimizu,et al.  Delayed assembly of desmosomes in keratinocytes with disrupted classic-cadherin-mediated cell adhesion by a dominant negative mutant. , 1995, The Journal of investigative dermatology.

[42]  M. Holick,et al.  The antiproliferative and differentiative activities of 1,25-dihydroxyvitamin D3 are potentiated by epidermal growth factor and attenuated by insulin in cultured human keratinocytes. , 1995, The Journal of investigative dermatology.