Clinical Utility of 1,25-Dihydroxyvitamin D 3 and Its Analogs for the Treatment of Psoriasis and Other Skin Diseases

Abstract

Vitamin D is photochemically sythesized by ultraviolet (UV)B action in the skin (1, 2). It is now known that the skin itself is a target tissue for the secosteroid hormone 1 α,25-dihydroxyvitamin D3 [1,25(OH)2D3, calcitriol], the biologically active vitamin D metabolite (3,4). 1,25(OH)2D3 exerts genomic and nongenomic effects. Nongenomic effects of 1,25(OH)2D3 and its analogs are related to effects on intracellular calcium (5,6). In keratinocytes and other cell types, calcitriol rapidly increases free cytosolic calcium levels (5,6). Genomic effects of 1,25(OH)2D3 are mediated via binding to a nuclear receptor protein that is present in target tissues and binds 1,25(OH)2D3 with high affinity (K D 10−9−10−10 M) and low capacity (7,8). The human vitamin D receptor (VDR) has been cloned (9), and sequence analysis has demonstrated that this protein belongs to the superfamily of trans-acting transcriptional regulatory factors, which includes the steroid and thyroid hormone receptors and the retinoic acid receptors (9). Interaction of 1,25(OH)2D3 with VDR results in the phosphorylation of the receptor complex, which in turn activates the transcription of calcitriol-sensitive target genes, especially genes involved in cellular differentiation and proliferation. Recently, it was shown that VDRs require auxiliary factors for sufficient DNA binding (10). These auxiliary proteins were identified as the retinoid X receptors (RXR-α, -β,- γ), which were shown to heterodimerize with VDR, thus increasing the transcriptional function and DNA binding to the respective vitamin D response elements (VDRE) in the promotor region of target genes (10,11). In the skin, both VDR (Fig. 1) and RXR-α are expressed in keratinocytes, fibroblasts, Langerhans cells, sebaceous gland cells, endothelial cells, and most cell types related to the skin immune system (12,13). In vitro studies revealed that 1,25(OH)2D3 is extremely effective in inducing terminal differentiation and inhibiting the proliferation of cultured human keratinocytes in a dose-dependent manner (14–16). Additionally, 1,25(OH)2D3 acts on many cell types involved in immunologic reactions, including lymphocytes, macrophages, and Langerhans cells (17,18). Data on the effects of 1,25(OH)2D3 on the melanin pigmentation system are still conflicting, but most studies do not support the possibility that 1,25(OH)2D3 regulates melanogenesis in human skin (19).