Bioactive forms of vitamin D selectively stimulate the skin analog of the hypothalamus-pituitary-adrenal axis in human epidermal keratinocytes

Abstract

Ultraviolet radiation B stimulates both the production of vitamin D3 in the skin and the activation of the skin analog of the hypothalamic-pituitary-adrenal axis (HPA) as well as the central HPA. Since the role of vitamin D3 in the regulation of the HPA is largely unknown, we investigated the impact of 1,25(OH)2D3 and its noncalcemic analogs, 20(OH)D3 and 21(OH)pD, on the expression of the local HPA in human epidermal keratinocytes. The noncalcemic analogs showed similar efficacy to 1,25(OH)2D3 in stimulating the expression of neuropeptides, CRF, urocortins and POMC, and their receptors, CRFR1, CRFR2, MC1R, MC2R, MC3R and MC4R. Interestingly, unlike other secosteroids, the activity of 21(OH)pD did not correlate with induction of differentiation, suggesting a separate but overlapping mechanism of action. Thus, biologically active forms of vitamin D can regulate different elements of the local equivalent of the HPA with implications for the systemic HPA.

Differential and Overlapping Effects of 20,23(OH)2D3 and 1,25(OH)2D3 on Gene Expression in Human Epidermal Keratinocytes: Identification of AhR as an Alternative Receptor for 20,23(OH)2D3

“…The inclusion of these additional pathways could be secondary to the use of the same dimeric partner, RXR, and communication between receptors, or alternatively by activation by signaling pathways downstream of VDR. For example, it is already known that 1,25(OH) 2 D3 can selectively activate local elements of hypothalamo-pituitary adrenal axis in keratinocytes [ 71 ]. The significance of additional nuclear receptor signaling is out of the scope of this paper and is a goal of our future research.…”

“…20(OH)D3 and 20,23(OH) 2 D3 also attenuate the symptoms of skin fibrosis, rheumatoid arthritis and have photoprotective properties [ 8 , 19 , 23 , 64 , 65 ]. The CYP11A1-derived secosteroids have pleiotropic phenotypic effects that are cell-type–dependent [ 19 , 23 , 60 , 61 , 62 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. They can act as biased agonists of the VDR [ 19 , 60 , 76 , 77 ] and can act as inverse agonists on retinoic acid orphan receptors (ROR) α and γ [ 60 , 78 ].…”

The serum vitamin D metabolome: What we know and what is still to discover

“…They also showed moderate anti-leukemic effects [69]. 21(OH)pD (pregnacalciferol) also increased the sensitivity of keratinocytes to reactive oxygen species (ROS) [198] and stimulated the expression of elements of the hypothalamus-pituitaryadrenal axis in keratinocytes [199].…”

Beneficial Regulation of Cellular Oxidative Stress Effects, and Expression of Inflammatory, Angiogenic, and the Extracellular Matrix Remodeling Proteins by 1α,25-Dihydroxyvitamin D3 in a Melanoma Cell Line

“…We recently reported the inhibition of cellular oxidative stress effects and inflammation by vitamin D in non-irradiated, and UV radiated fibroblasts [29]. Vitamin D had been reported to inhibit oxidative stress, inflammation, angiogenesis and ECM remodeling in diverse cell types or tissue [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. We herein extend the beneficial effects of vitamin D to melanoma cells.…”