ABSTRACT

The epidermis is well known as the source of vitamin D3 production in the body. Less well known is that epidermal cells (keratinocytes) also produce the active metabolite of vitamin D3, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) (1), contain 1,25(OH)2D3 receptors (VDR) (2-4), and respond to 1,25(OH)2D3 with changes in proliferation and differentiation (3,5,6). Calcium is an important modulator of these pathways. Calcium decreases 1,25(OH)2D3 production and regulates the effects of 1,25(OH)2D3 on proliferation and differentiation (7). Calcium is, by itself, an important regulator of keratinocyte proliferation and differentiation (8,9), the effects of which are, in turn, modulated by 1,25(OH)2D3. Although much of our information about the role of calcium and 1,25(OH)2D3 comes from in vitro studies, a calcium gradient exists in the epidermis that appears to be an important regulator of proliferation and differentiation in vivo. Animals lacking the ability to produce 1,25(OH)2D3 have difficulty restoring this gradient if disrupted, and such animals show abnormalities in terminal differentiation of the epidermis even when placed on a high-calcium diet. Similarly, animals lacking the vitamin D receptor (VDR) also have an abnormality in epidermal differentiation. Furthermore, these VDR-null animals have an abnormality in hair follicle cycling, not seen in vitamin D-deficient animals or in those lacking the capacity to produce 1,25(OH)2D3. Thus, the epidermis is not only an essential source of vitamin D, but is a source and target for its biologically active metabolite 1,25(OH)2D3, and can be uniquely regulated by the VDR in a ligand-independent manner.