The Antiproliferative and Differentiative Activities of 1,25-Dihydroxyvitamin D3 Are Potentiated by Epidermal Growth Factor and Attenuated by Insulin in Cultured Human Keratinocytes

Abstract

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is a potent inhibitor of keratinocyte proliferation, as well as a stimulator of epidermal terminal differentiation. In the present studies, we investigated the influence of epidermal growth factor (EGF) and insulin on the antiproliferative and differentiation activities of 1,25(OH)2D3. Our results indicate the following: (1) EGF caused a dramatic potentiation of the 1,25(OH)2 D3-induced inhibition of 3H-thymidine incorporation into keratinocytes in a dose-dependent manner; (2) insulin acted antagonistically on the EGF-dependent potentiation of the 1,25(OH)2D3-induced antiproliferative activity; (3) transforming growth factor-alpha potentiated 1,25(OH)2D3-induced antiproliferative activity similar to EGF; (4) the EGF effect was not dependent upon 1,25(OH)2D3 receptor mRNA up-regulation; and (5) removal of insulin from medium supplemented with growth factors significantly potentiated the 1,25(OH)2D3-induced inhibition on the number of basal cells and the 1,25(OH)2D3-dependent cornified envelope formation. In conclusion, the antiproliferative activity of 1,25(OH)2D3 in cultured normal human keratinocytes is greatly enhanced by EGF or transforming growth factor-alpha and reduced by insulin. Insulin also inhibits 1,25(OH)2D3-induced terminal differentiation of cultured normal human keratinocytes.

Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials

“…It is possible that, among the frail subjects at risk of hip fracture, other deficiencies, such as vitamin D deficiency and phosphate deficiency due to low protein intake, should be corrected along with ensuring adequate calcium intake (17). Calcium carbonate or calcium citrate supplements can reduce phosphate absorption (43), which may be detrimental, because a balanced ratio of calcium to phosphate is needed for bone mineralization (44). Phosphate deficiency [defined as an intake 70% of adult recommended dietary allowance (700 mg/d)] is found in 10% of US women 60 y old and in 15% of US women 80 y old (45).…”

Effects of Vitamin D₃ on Keratinocyte Proliferation and Differentiation in vitro: Modulation by Ligands for Retinoic Acid and Retinoid X Receptors

“…Thus Gniadecki [28] has shown that l,25(OH)2D3 can either inhibit or stimulate DNA synthesis in human kératinocytes depending on the cul ture conditions. Furthermore, Chen et al [29] found that the addition of insulin to the culture medium reduced the antiprolifera tive and differentiation-promoting effect of l,25(OHhD3. In contrast, the addition of epi dermal growth factor to the culture medium potentiated the effect of l,25(OH)2D3.…”

Proliferation and Differentiation of Cultured Human Keratinocytes is Modulated by 1,25(OH)2D3 and Synthetic Vitamin D3 Analogues in a Cell Density‐, Calcium‐ and Serum‐Dependent Manner*

“…Transforming growth factor-p-1 is known to enhance the vitamin D antiproliferative effect in human keratinocytes (Kim et al 1992). Epidermal growth factor is reported to enhance vitamin D actions in keratinocytes (Chen et al 1995), but epidermal growth factor was already added to the keratinocyte growth medium together with bovine pituitary extract. Proteins such as vitamin D binding protein or albumin present in foetal calf serum may also act to stabilize the analogues and in this way enhance their activity.…”

“…However, the potency of the vitamin D analogues differs from one cell type to another. Also, it appears that the sensitivity to the vitamin D analogues may be dependent on the presence of serum (Imai et al 1995), growth factors (Chen et al 1995;Gniadecki 1996; Kim et al 1992) and the concentration of calcium (Gniadecki 1996;Itin et al 1994;Su et al 1994). Furthermore, in vivo studies of epidermal proliferation indicate that the direction of the response to vitamin D3 analogues is dependent on the proliferative state of the epidermis.…”