Ligand-Independent Vitamin D Receptor Actions Essential for Keratinocyte Homeostasis in the Skin

Recently, we demonstrated that the alopecia observed in vitamin D receptor gene deficient (VDR-KO) rats is not seen in rats with a mutant VDR (R270L/H301Q), which lacks ligand-binding ability, suggesting that the ligand-independent action of VDR plays a crucial role in maintaining the hair cycle. Since VDR-KO rats also showed abnormalities in the skin, the relationship between alopecia and skin abnormalities was examined. To clarify the mechanism of actions of vitamin D and VDR in the skin, protein composition, and gene expression patterns in the skin were compared among VDR-KO, VDR (R270L/H301Q), and wild-type (WT) rats. While R270L/H301Q rats exhibited normal skin formation similarly to WT rats, VDR-KO rats showed a remarkable hyperkeratosis and trans-epidermal water loss in the skin. RNA sequencing and proteomic analysis revealed that the gene and protein expression patterns in VDR-KO rats significantly differed from those in WT and VDR (R270L/H301Q) rats, with a marked decrease in the expression of factors involved in Shh, Wnt, and Bmp signaling pathways, a dramatic reduction in the expression of hair keratins, and a substantial increase in the expression of epidermal keratins. This study clearly demonstrated that non-liganded VDR is significantly involved in the differentiation, proliferation, and cell death of keratinocytes in hair follicles and the epidermis.