*Monika Bilewicz-Stebel1, Beata Bergler-Czop2, Katarzyna Sierant3, Dominika Wcisło-Dziadecka4
Vitamin D in dermatology
Witamina D w dermatologii
1Department of Internal Medicine, Dermatology and Allergology, Specialized Hospital in Zabrze
Head of Department: Professor Jerzy Jarząb, MD, PhD
2Department of Dermatology, School of Medicine in Katowice, Medical University of Silesia in Katowice
Head of Department: Professor Ligia Brzezińska-Wcisło, MD, PhD
3Chair and Department of Dermatology, Andrzej Mielęcki Silesian Independent Public Hospital in Katowice
Head of Department: Professor Ligia Brzezińska-Wcisło, MD, PhD
4Department of Skin Structural Studies, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice
Head of Department: Krzysztof Jasik, assistant professor
Witamina D pierwotnie znana była ze swej roli w utrzymaniu prawidłowej gospodarki kostnej poprzez regulację metabolizmu parathormonu (PTH), wapnia i fosforu, zapewniając integralność układu kostnego. W ostatnich dziesięcioleciach witamina D ponownie wzbudziła uwagę badaczy z powodu swojego wpływu na wiele zaburzeń zdrowotnych. Badania potwierdziły jej ingerencję w prawidłowe funkcjonowanie większości tkanek w organizmie człowieka, m.in. mózgu, sercu, mięśniach, układzie odpornościowym, a także w skórze. Wskazanie wielu nowych aktywności witaminy D było możliwe dzięki odkryciu obecności receptora witaminy D (VDR) w większości komórek organizmu i enzymów, które syntetyzują aktywną formę witaminy w innych niż nerkowe tkankach, zwłaszcza w skórze. Doprowadziło to do poszukiwania, jaką rolę odgrywa witamina D w zmniejszaniu ryzyka przewlekłych i śmiertelnych stanów chorobowych, takich jak: nowotwory, choroby autoimmunologiczne i zakaźne czy choroby układu krążenia. Zasadniczo uwaga dermatologów skupiała się na znaczeniu witaminy D w łuszczycy, ale prowadzone badania poszerzają jej terapeutyczne wskazania w chorobach skórnych, takich jak nowotwory czy atopowe zapalenie skóry.
Vitamin D was primarily acknowledged for its role in bones formation by regulating parathyroid hormone (PTH), calcium and phosphorous metabolism leading to maintain the integrity of the skeletal system. Over the past decades, once more the vitamin D attracted a great attention because of its implication in a numerous medical disorders. Researches confirmed its interference in the proper functioning of the most tissues in human body including brain, heart, muscles, immune system and also the skin. Pointing multiple new roles of the vitamin was possible because of discovery of vitamin D receptors (VDRs) in most cells of the body and the presence of enzymes that synthesize the active form of vitamin D in other than renal tissue, especially in the skin. It led to an interest in its role in decreasing the risk of chronic, highly morbid conditions such as carcinomas, autoimmune diseases, infectious diseases and cardiovascular diseases. Basically, its importance for dermatologists focused on its significance in psoriasis but further researches broadens its therapeutic effects in skin diseases such as skin cancers or atopic dermatitis.
Vitamin D3 – chemically 1α,25-dihydroxycholecalciferol – is an organic steroid substance, historically classified as a vitamin, in fact being a hormonal compound. Its precursor – cholesterol – is a steroid lipid compound supplied to the human organism with food (exogenous cholesterol) or produced in a process of biosynthesis (endogenous cholesterol) (1, 2). At the basal layer of epidermis, the cholesterol is converted to provitamin D3 (7-dehydrocholesterol), which undergoes a photochemical transformation due to ultraviolet B radiation (UVB) into the intermediate compound previtamin D3. Then a slow isomerization process under the influence of temperature results in a production of cholecalciferol (traditionally called vitamin D3), lumisterol and tachysterol. This process takes place at UVB range between 290-320 nm, with the pick reaction at 297 nm. The process is presented at the figure 1. It is estimated that cholecalciferol biosynthesis in the skin covers 80-100% of the vitamin D demand. In the vitamin D metabolic pathway exists the reaction which protects against the formation of toxic amounts of this substance during a prolonged UVB exposure. It is a mechanism of increased production and accumulation of lumisterol, at the expense of vitamin D and tachysterol. But beyond skin biosynthesis, vitamin D is also delivered by absorption in the intestines from food and dietary supplements or medical products (3).
Fig. 1. Cycle of skin conversion 7-dehydrocholesterol to cholecalciferol – vitamin D3 (3)
Vitamin D3 is a form of prohormone – a chemical compound with a very low activity. It can be converted into a fully active hormone by enzymatic and non-enzymatic photochemical processes. Cholecalciferol synthesized in the skin is transferred to a circulatory system. The first activation is made in hepatic cells into 25-hydroxycholecalciferol – calcidiol [25(OH)D], which is the main form of vitamin circulating in the blood. The second stage occurs in the kidney cells with production of 1α,25-dihydroxycholecalciferol – calcitriol [1,25(OH)D], which is the main active form of the vitamin and a specific ligand for a nuclear vitamin D receptor (VDR). The receptor was initially found in intestinal epithelial cells, renal cells and bone tissue. For this reason, vitamin D was perceived by its activity in the calcium-phosphate and bone mineral metabolism (1). Researches which discovered the presence of VDR in most tissues of the human body made an increased interest in vitamin D action and underlined its importance in numerous diseases (3, 4). Vitamin D deficiency is a proved risk factor for such affection as cancers, skin diseases, autoimmune diseases, type 1 and type 2 diabetes mellitus, cardiovascular disease, hypertension, metabolic or infectious diseases, neurological syndromes and mental disorders (4, 5).
1,25(OH)D induces its endocrine effects on target tissues by intracrine, autocrine and paracrine routes in two ways – by modifying transcription of genes (genomic mechanism) and non-transcription (non-genomic mechanism) (1, 3).
Gene transcription is effected via binding calcitriol to VDR in the target cell cytoplasm what initiates the intracellular heterodimerization of VDR and the retinoic X receptor (RXR) leading to form a complex able to penetrate into the cell nucleus. Formed VDR-RXR heterodimer is capable to recognize specific DNA sequences – the VDRE (vitamin D response element) and along with multiple regulatory proteins, impacts the gene transcription, mainly by chromatin acetylation (4, 6). This process may result in the activation or inhibition of gene expression. The inhibition is probably responsible for anti-inflammatory and anti-proliferative features of the vitamin (3, 7).
As a non-transcriptional pathway the literature describes the ability of 1,25-dihydroxycholecalciferol to affect intracellular calcium levels, as well as intracellular signaling kinases and phosphatases. The facility of activation different pathways in different types of cells confirmed the pleiotropic features of vitamin D (7-9).
Vitamin D within the skin exerts control of cell proliferation, differentiation and maturation, control of angiogenesis, regulation of cellular apoptosis, induction of tumor cell differentiation, participation in the process of epidermal barrier renewal. The most recent literature reports highlight the immunomodulating effect of this compound, including stimulating immune system cell differentiation and inhibiting the production of proinflammatory cytokines that contribute to the development and progression of inflammatory process in skin diseases (10, 11).
Because of the proven impact of vitamin D on numerous disorders and its multiple activities, it is important to sick for its role in skin diseases.
Vitamin D and psoriasis
Psoriasis is a chronic immune-mediated inflammatory skin disease that affects about 2-3% of the general population (12). Although the countless researches, the pathogenesis of psoriasis is still not fully known. Evidences suggest the dysregulation of the immune cells in the skin, especially lymphocyte T cells (2). Characteristic histopathological image shows hyperproliferation associated with incomplete differentiation of keratinocytes and decreased keratinocyte apoptosis, skin infiltration by activated inflammatory cells and impaired epidermal barrier function at the sites of skin lesions (2, 12).
Studies which focused on the possible role of vitamin D in psoriasis show several pathways of possible mechanism (13-15). It involves the anti-proliferative function of vitamin D – human keratinocytes exposed to an active form of the vitamin showed inhibition of growth and faster maturation (16). Moreover, the anti-inflammatory and anti-angiogenic activity of calcitriol counteract with inflammation and angiogenesis present in psoriatic lesions. It suppresses the proinflammatory Th1 and Th17 cell proliferation, as well as induce the regulatory T cells.
Topically used vitamin D analogues significantly decreases cutaneous levels of proinflammatory IL-17 and IL-8 (2, 17). In addition, dendritic cells differentiation, maturation and antigen presentation seem to be reduced by active 1,25(OH)D (12).
Anti-inflammatory effects exhibit a role of systemic vitamin D deficiency in the pathogenesis of psoriasis. Recent studies have shown that its level is significantly lower in psoriatic patients than in control groups (14, 18). Aside these reports, some review researches point that the significance of low serum vitamin D level in psoriasis is unknown and the legitimacy of vitamin supplementation is unclear. It states a question if a low level of cholecalciferol is a cause or a result of the underlying illness, citing the fact that low serum vitamin levels are also widely observed in the general population (19). Probable supplementation benefits are expected in patients with additional comorbidities such as risk of reduced bone mineral density (20).
Vitamin D and skin cancer
UV radiation is indispensable in the process of formation approximately 80-90% of all required vitamin D. Simultaneously, UV radiation is the most important environmental carcinogen associated with increased risk of photocarcinogenesis of skin cancer. The risk applies to melanomas and two non-melanomas types: basal-cell carcinomas (BCC) and squamous-cell carcinomas (SCC) (21, 22). Calcitriol would be beneficial as it stimulates the differentiation of epidermal keratinocytes leading to prevent form developing malignancies in affected cells (23). Moreover, studies on cell cultures in vitro and mouse studies with topically applied vitamin D to the skin revealed that vitamin D shows photoprotective effects by decreasing DNA damage, reducing apoptosis, increasing cell survival and decreasing erythema (24-26). On the other hand, researches revealed that malignantly transformed cells may be resistant to active form of vitamin D and e.g. SCC failed to respond to calcitriol in prodifferentiating effect. Surprisingly, these cells had normal expression of VDR and appropriate binding to response elements (23). Besides, Caini et al. did not find that vitamin D intaken from diet or supplements has any protective effect against skin cancer development (27).
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