Lack of the Vitamin D Receptor is Associated with Reduced Epidermal Differentiation and Hair Follicle Growth

Abstract

The active vitamin D metabolite, 1,25-dihydroxyvitamin D, acting through the vitamin D receptor, regulates the expression of genes in a variety of vitamin D-responsive tissues, including the epidermis. To investigate the role of the vitamin D receptor in mediating epidermal differentiation, we examined the histomorphology and expression of differentiation markers in the epidermis of vitamin D receptor knockout mice generated by gene targeting. The homozygous knockout mouse displayed a phenotype that closely resembles vitamin D-dependent rickets type II in humans, including the development of rickets and alopecia. Hair loss developed by 3 mo after birth and gradually led to nearly total hair loss by 8 mo. Histologic analysis of the skin of homozygous knockout mice revealed dilation of the hair follicles with the formation of dermal cysts starting at the age of 3 wk. These cysts increased in size and number with age. Epidermal differentiation markers, including involucrin, profilaggrin, and loricrin, detected by immunostaining and in situ hybridization, showed decreased expression levels in homozygous knockout mice from birth until 3 wk, preceding the morphologic changes observed in the hair follicles. Keratin 10 levels, however, were not reduced. At the ultrastructural level, homozygous knockout mice showed increased numbers of small dense granules in the granular layer with few or no surrounding keratin bundles and a loss of keratohyalin granules. Thus, both the interfollicular epidermis and the hair follicle appear to require the vitamin D receptor for normal differentiation. The temporal abnormalities between the two processes reflect the apparent lack of requirement for the vitamin D receptor during the anagen phase of the first (developmental) hair cycle, but with earlier effects on the terminal differentiation of the interfollicular epidermis.

Evaluation of 25 hydroxy vitamin D3 levels in patients with alopecia areata

“…VDR insan ve sıçan kıl folüküllerinde yoğun olarak eksprese edilir 2 . VDR yoksun edilmiş sıçanlarda ve herediter 1,25 dihidroksi vitamin D3 dirençli rikets tip 2'li hastalarda sağlıklı kıl döngüsü oluşmaz ve alopesi izlenir [5][6][7] . Bu bulgular kıl folüküllerinin sağlıklı gelişimi için D vitaminin gerekliliğini ortaya koymaktadır.…”

TRPV6 Is a Ca2+ Entry Channel Essential for Ca2+-induced Differentiation of Human Keratinocytes

“…The 1,25-dihydroxyvitamin D3 receptor (VDR) is critical for the genomic actions of 1,25-dihydroxyvitamin D3 (18). VDR-null mice have also been shown experimentally to exhibit a defect in epidermal differentiation, demonstrated by reduced levels of involucrin (IVL), profilaggrin, and loricrin, as well as the loss of keratohyalin granules (19). Thus, 1,25-dihydroxyvitamin D3 also appears to be one of the key regulators of keratinocyte differentiation in vivo.…”

Identification of vitamin D receptor as a target of p63

“…VDR primarily regulates the expression of genes involved in calcium homeostasis and differentiation (Banerjee and Chatterjee, 2003;Christakos et al, 2003;Guzey et al, 2004). VDR is expressed in the basal layers of keratinocytes and plays an important role in regulating the differentiation and proliferation of epidermal cells (Xie et al, 2002;Bikle, 2004;Bikle et al, 2004). Recently, VDR was shown to regulate genes known to play a role in differentiation of keratinocytes by binding directly to its cognate binding sites on promoter regions (Bikle et al, 2003;Lu et al, 2005).…”