25 Hydroxyvitamin D 1 α-Hydroxylase Is Required for Optimal Epidermal Differentiation and Permeability Barrier Homeostasis

Abstract

Keratinocytes express high levels of 25OHD 1alpha-hydroxylase (1OHase). The product of this enzyme, 1,25-dihydroxyvitamin D (1,25(OH)(2)D), promotes the differentiation of keratinocytes in vitro suggesting an important role for this enzyme in epidermal differentiation. To test whether 1OHase activity is essential for keratinocyte differentiation in vivo we examined the differentiation process in mice null for the expression of the 1alphaOHase gene (1alphaOHase(-/-)). Heterozygotes for the null allele were bred, and the progeny genotyped by PCR. The epidermis of the 1alphaOHase(-/-) animals and their wild-type littermates (1alphaOHase(+/+)) were examined by histology at the light and electron microscopic level, by immunocytochemistry for markers of differentiation, and by function examining the permeability barrier using transepidermal water loss (TEWL). No gross epidermal phenotype was observed; however, immunocytochemical assessment of the epidermis revealed a reduction in involucrin, filaggrin, and loricrin-markers of differentiation in the keratinocyte and critical for the formation of the cornified envelope. These observations were confirmed at the electron microscopic level, which showed a reduction in the F (containing filaggrin) and L (containing loricrin) granules and a reduced calcium gradient. The functional significance of these observations was tested using TEWL to evaluate the permeability barrier function of the epidermis. Although TEWL was normal in the basal state, following disruption of the barrier using tape stripping, the 1alphaOHase(-/-) animals displayed a markedly delayed recovery of normal barrier function. This delay was associated with a reduction in lamellar body secretion and a failure to reform the epidermal calcium gradient. Thus, the 25OHD 1OHase is essential for normal epidermal differentiation, most likely by producing the vitamin D metabolite, 1,25(OH)(2)D, responsible for inducing the proteins regulating calcium levels in the epidermis that are critical for the generation and maintenance of the barrier.

Cytochrome P450-mediated metabolism of vitamin D

“…Detailed bone histomorphometric analyses of the CYP27B1 and CYP27B1/PTH double-knockout mice established that 1,25-(OH) 2 D 3 defi ciency resulted in epiphyseal dysgenesis and only minor changes in trabecular bone volume ( 87 ). Bikle and colleagues showed that CYP27B1 is also required for optimal epidermal differentiation and permeability barrier homeostasis in the skin of mice ( 88 ). Administration of a normal diet supplemented with either small amounts of 1,25-(OH) 2 D 3 or use of a high-calcium "rescue diet" largely corrects the mineral metabolism and bone defects seen in the CYP27B1-null mouse (89)(90)(91)(92).…”

Evidence for 1,25-Dihydroxyvitamin D3-independent Transactivation by the Vitamin D Receptor

“…These anomalies are not corrected by a high calcium diet, indicating that they are due to direct actions of VDR in keratinocytes. In contrast, the skin and hair of 1␣OHaseKO mice appears to be morphologically normal and exhibits only minor differences in expression of skin differentiation markers compared with wild type controls (26). Thus, in animals lacking the 1,25(OH) 2 D 3 ligand, hair follicle cycling and keratinocyte proliferation are normal.…”

Vitamin D Deficiency Rickets in an Adolescent With Severe Atopic Dermatitis

“…22 In addition, VD is relevant for epidermal differentiation and skin barrier permeability, essential factors that are altered in patients with AD. 23 Current treatments of AD are focused on decreasing skin inflammation and improving barrier function, but no safe and effective oral treatment has been demonstrated. VD is a low-cost intervention that is safe and easy to administer in any setting and at any age.…”