The 1,25-dihydroxyvitamin D3-independent actions of the vitamin D receptor in skin

The vitamin D endocrine system plays important but poorly understood roles in the skin and in hair follicle cycling. Rare, human genetic disorders and knockout mouse models highlight essential roles and potentially novel mechanisms of the vitamin D endocrine system in the skin. Vitamin D receptor knockout mice express a hair follicle cycling defect and a hyperproliferative phenotype resulting in disordered skin structure, epidermal thickening, and alopecia. In contrast, ligand knockout mice (i.e., mice with a disrupted CYP27B1 gene that encodes the 25-hydroxyvitamin-D3 1alpha-hydroxylase) have normal hair follicle function and a comparatively modest skin phenotype. These disparate models indicate that VDR may function independently of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in regulating hair follicle cycling and skin biology. Recent studies highlight this concept and provide key support for this hypothesis. While VDR knockout mice are highly susceptible to chemically induced skin tumorigenesis, CYP27B1 knockouts are resistant. These studies reveal a second global physiological process in the skin that may be regulated by VDR in a 1,25(OH)2D3-independent fashion, namely, genoprotection against carcinogenic mutagens. Key cellular and molecular data supporting this mechanism were published recently showing a keratinocyte-selective transactivation activity mediated by VDR that is independent of the 1,25(OH)2D3 ligand. Thus, evidence is building to support a potentially novel, 1,25(OH)2D3-independent mechanism through which VDR functions in keratinocytes and perhaps within stem cell populations in the follicle to regulate genoprotection and other key developmental processes in the skin.