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.