Role of vitamin D in skin and hair biology

The major cell of the epidermis is the keratinocyte. Its proliferation and differentiation are regulated by 1,25-dihydroxyvitamin D (1,25(OH)2D) and calcium acting through their respective receptors, the vitamin D receptor (VDR) and the calcium-sensing receptor. The keratinocyte makes its own 1,25(OH)2D from the vitamin D produced in the skin. The epidermis maintains a steep calcium gradient with the highest concentration in the stratum granulosum. VDR and CYP27B1 have their highest expression in the stratum basale. Calcium and 1,25(OH)2D have overlapping and generally synergistic effects on keratinocyte proliferation and differentiation. Control of the different stages of differentiation is mediated in part via the differential distribution of coactivators. In the absence of VDR the epidermis in prone to tumor formation through a number of mechanisms including loss of the E-cadherin/catenin complex important for calcium signaling, decreased DNA damage repair, activation of hedgehog signaling, and abnormalities in beta-catenin signaling. Similarly, loss of VDR in conjunction with low calcium reduces stem cell activation thus delaying the epidermal response to wounding. Mutations of the vitamin D receptor in humans and mice lead to alopecia due to impaired cyclic regeneration of the hair follicle. Alopecia is not observed with vitamin D deficiency or absence of CYP27B1, the enzyme required for activation of vitamin D metabolites. Thus, unlike the effects of the vitamin D receptor on epidermal keratinocytes, which are largely ligand dependent, the actions of the vitamin D receptor that are essential for cyclic regeneration of the hair follicle do not require 1,25(OH)2D.