Application Of Calcitriol Research Articles

Calcitriol, an Active Form of Vitamin D3, Mitigates Skin Barrier Dysfunction in Atopic Dermatitis NC/Nga Mice.

Atopic dermatitis and psoriasis are prevalent chronic inflammatory skin diseases that are characterized by dysfunctional skin barriers and substantially impact patients' quality of life. Vitamin D3 regulates immune responses and keratinocyte differentiation and improves psoriasis symptoms; however, its effects on atopic dermatitis remain unclear. Here, we investigated the effects of calcitriol, an active form of vitamin D3, on an NC/Nga mouse model of atopic dermatitis. We observed that the topical application of calcitriol decreased the dermatitis scores and epidermal thickness of NC/Nga mice with atopic dermatitis compared to untreated mice. In addition, both stratum corneum barrier function as assessed by the measurement of transepidermal water loss and tight junction barrier function as evaluated by biotin tracer permeability assay were improved following calcitriol treatment. Moreover, calcitriol treatment reversed the decrease in the expression of skin barrier-related proteins and decreased the expression of inflammatory cytokines such as interleukin (IL)-13 and IL-33 in mice with atopic dermatitis. These findings suggest that the topical application of calcitriol might improve the symptoms of atopic dermatitis by repairing the dysfunctional epidermal and tight junction barriers. Our results suggest that calcitriol might be a viable therapeutic agent for the treatment of atopic dermatitis in addition to psoriasis.

Calcitriol-enhanced autophagy in gingival epithelium attenuates periodontal inflammation in rats with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM)-associated periodontitis is a common disease with high prevalence, associated with persistent infection and complicated manifestations. Calcitriol (1 alpha, 25-dihydroxyvitamin D3, 1,25D) is the active form of vitamin D that plays a protective role in immune regulation, bone metabolism, and inflammatory response. In this study, we constructed a T2DM model in rats by combining a high-fat diet with low-dose streptozotocin. The periodontitis model in rats was developed by ligation and Porphyromonas gingivalis (ATCC 33277) inoculation. Rats were randomly divided into five groups: non-diabetic blank, diabetic blank, diabetes with calcitriol treatment, diabetes with 3-methyladenine (3-MA) treatment, or diabetes with calcitriol and 3-MA treatment. The diabetic rats exhibited an intense inflammatory response and decreased autophagy compared with the non-diabetic rats. Intraperitoneal injection of calcitriol and autophagy inhibitor (3-MA) allowed us to explore the effect of calcitriol on inflammation in the gingival epithelium and the role of autophagy in this process. Treatment with calcitriol resulted in the decreased expression of NFκB-p65, p62/SQSTM1 and inflammatory response and increased expression of LC3-II/LC3-I. Application of 3-MA significantly suppressed autophagy, which was apparently retrieved by calcitriol. Antibacterial peptide (LL-37) is the only antimicrobial peptide in the cathelicidin family that is found in the human body, and it exhibits a broad spectrum of antibacterial activity and regulates the immune system. In the present study, our findings indicated that calcitriol-enhanced autophagy may attenuated periodontitis and the decrease of LL-37 was rescued by calcitriol treatment in the gingival epithelial cells of T2DM rats. Our study provides evidence for the application of calcitriol as an adjunctive treatment for T2DM-associated periodontitis.

Bioactive Vitamin D Attenuates MED28-Mediated Cell Growth and Epithelial–Mesenchymal Transition in Human Colorectal Cancer Cells

Inadequate vitamin D status may increase the risk of developing multiple types of cancer. Epidemiological studies suggest an inverse association between 25-hydroxyvitamin D3 (25(OH)D3) and malignancy, including colorectal cancer. Previous studies have suggested that MED28, a Mediator subunit involved in transcriptional regulation, is associated with the growth of colorectal cancer cells; however, its role in the progression of metastasis such as epithelial–mesenchymal transition (EMT) and cell migration of colorectal cancer is unclear at present. The aim of this study was to investigate a potentially suppressive effect of calcitriol, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), a bioactive form of vitamin D, and the role of MED28 in the progression of EMT in human colorectal cancer cells. Suppression of MED28 increased the expression of E-cadherin and reduced the expression of several mesenchymal and migration biomarkers and Wnt/β-catenin signaling molecules, whereas overexpression of MED28 enhanced the EMT features. Calcitriol suppressed the expression of MED28, and the effect of calcitriol mirrored that of MED28 silencing. Our data indicate that calcitriol attenuated MED28-mediated cell growth and EMT in human colorectal cancer cells, underlining the significance of MED28 in the progression of colorectal cancer and supporting the potential translational application of calcitriol.

Calcitriol Alleviates MPP+- and MPTP-Induced Parthanatos Through the VDR/PARP1 Pathway in the Model of Parkinson's Disease.

The pathogenesis of Parkinson’s disease (PD) is currently unclear. Recent studies have suggested a correlation between vitamin D and PD. Vitamin D and its analogs have protective effects in animal models of PD, but these studies have not clarified the mechanism. Parthanatos is a distinct type of cell death caused by excessive activation of poly (ADP-ribose) polymerase-1 (PARP1), and the activation of PARP1 in PD models suggests that parthanatos may exist in PD pathophysiology. 1,25-Dihydroxyvitamin D3 (calcitriol) is a potential inhibitor of PARP1 in macrophages. This study aimed to investigate whether calcitriol treatment improves PD models and its effects on the parthanatos pathway. A 1-methyl-4-phenylpyridinium (MPP+)-induced cell model and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) subacute animal model were selected as the in vitro and in vivo PD models, and calcitriol was applied in these models. Results showed that parthanatos existed in the MPP+-induced cell model and pretreatment with calcitriol improved cell viability, reduced the excessive activation of PARP1, and relieved parthanatos. The application of calcitriol in the MPTP subacute animal model also improved behavioral tests, restored the damage to dopamine neurons, and reduced the activation of PARP1-related signaling pathways. To verify whether calcitriol interacts with PARP1 through its vitamin D receptor (VDR), siRNA, and overexpression plasmids were used to downregulate or overexpress VDR. Following the downregulation of VDR, the expression and activation of PARP1 increased and PARP1 was inhibited when VDR was overexpressed. Coimmunoprecipitation verified the combination of VDR and PARP1. In short, calcitriol can substantially improve parthanatos in the MPP+-induced cell model and MPTP model, and the protective effect might be partly through the VDR/PARP1 pathway, which provides a new possibility for the treatment of PD.

Topical calcitriol application promotes diabetic corneal wound healing and reinnervation through inhibiting NLRP3 inflammasome activation

Vitamin D (VD) deficiency delays corneal wound healing in those with diabetes, which cannot be rescued with supplemental diet. Here, we employed topical calcitriol application to evaluate its efficiency in corneal wound healing and reinnervation in diabetic mice. Type 1 diabetic mice were topically administrated calcitriol, or subconjunctivally injected with NLRP3 antagonist MCC950 or IL-1β blocking antibody after epithelial debridement. Serum VD levels, corneal epithelial defect, corneal sensation and nerve density, NLRP3 inflammasome activation, neutrophil infiltration, macrophage phenotypes, and gene expressions were examined. Compared with those of normal mice, diabetic mice showed reduced serum VD levels. Topical calcitriol application promoted corneal wound healing and nerve regeneration, as well as sensation recovery in diabetic mice. Moreover, calcitriol ameliorated neutrophil infiltration and promoted the M1-to-M2 macrophage transition, accompanied by suppressed overactivation of the NLRP3 inflammasome. Treatment with NLRP3 antagonist or IL-1β blockage demonstrated similar improvements as those of topical calcitriol application. Additionally, calcitriol administration upregulated desmosomal and hemidesmosomal gene expression in the diabetic cornea. In conclusion, topical calcitriol application promotes corneal wound healing and reinnervation during diabetes, which may be related to the suppression of the overactivation of NLRP3 inflammasome.

Sequential treatment with calcitriol and methyl aminolevulinate-daylight photodynamic therapy for patients with multiple actinic keratoses of the upper extremities

BackgroundTopical photodynamic therapy (PDT) is a widely used and effective treatment for actinic keratoses (AKs). However, cure rates are significantly reduced for AKs on acral sites. We compared the sequential regimen of topical calcitriol and methyl aminolevulinate (MAL) daylight-PDT (CAL-DL-PDT) versus placebo and MAL-DL-PDT (P-DL-PDT) on acral AKs in an intra-individual, randomized trial. MethodsAdult patients with multiple all grade AKs of the upper extremities were treated with daily topical calcitriol or placebo for 14 days followed by 2 sessions of DL-MAL-PDT. After 3 months, patients were evaluated for lesion response rate, both overall and by AK grade, and patient ≥ 75 % clearance rate. Safety assessments included pain VAS immediately after the first DL-PDT session, side effects after calcitriol pretreatment and 7 days after the first DL-PDT session. Cosmetic outcome by the physician and patient’s preference were graded at the end of the study. ResultsForty-two patients were enrolled and 36/42 completed the study. After 3 months, the overall lesion response rate and patient ≥ 75 % clearance rate of CAL-DL-PDT were higher, albeit not significantly, than P-DL-PDT. According to grade, response rate of grouped AK II/III was significantly higher for CAL-DL-PDT than for P-DL-PDT while similar results were observed for grade I AKs. Mild erythema and itch were reported after calcitriol application. No significant difference was observed in pain intensity. Local skin reactions occurred more frequently on the CAL-DL-PDT-treated sides. Cosmetic outcome did not differ but overall subject’s preference was slightly significantly in favor of P-DL-PDT. ConclusionsCAL-DL-PDT is more effective than P-DL-PDT for thicker “difficult to treat” AKs on the upper extremities but is associated with increased local skin reactions.

Investigation of mineral bone disorders in pre-dialysis patients with chronic kidney disease

Objective To investigate mineral bone metabolic conditions of pre-dialysis patients with chronic kidney disease (CKD), and obtain useful information about the management and treatment of CKD. Methods The levels of serum calcium, phosphate, 25-HydroxyvitaminD[25(OH)VitD], and intact parathyroid hormone (iPTH) were compared. Then a correlation analysis was performed for 25(OH)VitD. Results Hypocalcemia, hyperphosphatemia, secondary hyperparathyroidism and inadequate of 25(OH)VitD appeared early in CKD2. Deficiency of 25(OH)VitD was widespread in CKD2~5. Multiple linear regression analysis showed that 25(OH)VitD was independently associated with adjusted level of calcium (P=0.002), application of calcium carbonate (P=0.038), and application of calcitriol (P=0.049) (R square=0.360, P=0.000). Conclusions Mineral bone disorder emerges early in CKD2. More attention should be paid to the management of 25(OH)VitD. Key words: Kidney diseases/ME; Minerals/ME; Vitamin D/ME

Protective Effect of Topical Vitamin D3 against Photocarcinogenesis in a Murine Model.

BackgroundAlthough the incidence of non-melanoma skin cancer is increasing, there are no effective practical preventive measures other than avoiding sun exposure.ObjectiveTo elucidate the protective effect of topical application of biologically active vitamin D3 (calcitriol) on skin cancer development caused by exposure to ultraviolet (UV).MethodsGroups of hairless mice were topically treated with either calcitriol or vehicle immediately after exposure to UVB and UVA three times weekly for the initial 20 weeks, and without UV exposure in the following 6 weeks. Tumor number was counted and biopsies were done for histopathologic analysis. The changes of cyclobutane pyrimidine dimer (CPD) were evaluated 1 hour and 11 hours after short term of UV exposure and application of calcitriol. For safety evaluation, blood test and body weights were evaluated at 23rd and 25th week.ResultsTotal tumor count and number of tumors less than 3 mm in size tended to be fewer in calcitriol group, and tumors more than 3 mm in size showed significantly lower tumor formation rate in calcitriol group. Single application of calcitriol reduced CPD at 1 hour and 11 hours after UV exposure. Histopathologic analysis showed tumors with lower grade malignancy in calcitriol group which suggested a delay in tumor progression. However, serum levels of calcium and phosphate in calcitriol group were above normal range, and weight loss was found.ConclusionTopical calcitriol may suppress the formation and progression of UV-induced non-melanoma skin cancer by enhancing the repair mechanism of UV damage.

An open label pilot study of supraerythemogenic excimer laser in combination with clobetasol spray and calcitriol ointment for the treatment of generalized plaque psoriasis

A common therapeutic modality for psoriasis includes the combination of phototherapy with topical treatments. The recent development of targeted phototherapy with the excimer laser and spray formulations for topical treatments has increased the efficacy and convenience of these combinational therapies. Herein, we aim to assess the efficacy of a novel combination of therapies using the 308 nm excimer laser, clobetasol propionate spray and calcitriol ointment for the treatment of moderate to severe generalized psoriasis. In this 12-week study, patients with moderate to severe psoriasis received twice weekly treatments with a 308-nm excimer laser combined with clobetasol proprionate twice daily for a month followed by calcitriol ointment twice daily for the next month. Of the 30 patients enrolled, 83% of patients (25/30) achieved PASI-75 [65–94%, 95% confidence interval (CI)] at week 12. For PGA, there was an estimated decrease of 3.6 points (3.1–4.1, 95% CI, p < 0.0005) by week 12. In conclusion, the combination of excimer laser with alternating clobetasol and calcitriol application has shown to be a promising combination of therapies for the treatment of moderate to severe generalized psoriasis. Further evaluation may be conducted with a larger study inclusive of control groups and head-to-head comparisons against topical steroid and UVB therapy as monotherapies.

TSLP is differentially regulated by vitamin D3 and cytokines in human skin.

Thymic stromal lymphopoietin (TSLP) plays an important role in allergic diseases and is highly expressed in keratinocytes in human lesional atopic dermatitis (AD) skin. In nonlesional AD skin TSLP expression can be induced by applying house dust mite allergen onto the skin in the atopy patch test. Several studies have demonstrated that the induction of TSLP expression in mouse skin does not only lead to AD-like inflammation of the skin, but also predisposes to severe inflammation of the airways. In mice, TSLP expression can be induced by application of the 1,25-dihydroxyvitamin D3 (VD3) analogue calcipotriol and results in the development of eczema-like lesions. The objective is to investigate the effect of VD3 (calcitriol) or calcipotriol on TSLP expression in normal human skin and skin from AD patients. Using multiple ex vivo experimental setups, the effects of calci(po)triol on TSLP expression by normal human skin, and skin from AD patients were investigated and compared to effects of calcipotriol on mouse and non-human primates (NHP) skin. No induction of TSLP expression (mRNA or protein) was observed in human keratinocytes, normal human skin, nonlesional AD skin, or NHP skin samples after stimulation with calcipotriol or topical application of calcitriol. The biological activity of calci(po)triol in human skin samples was demonstrated by the increased expression of the VD3-responsive Cyp24a1 gene. TSLP expression was induced by cytokines (IL-4, IL-13, and TNF-α) in skin samples from all three species. In contrast to the findings in human and NHP, a consistent increase in TSLP expression was confirmed in mouse skin biopsies after stimulation with calcipotriol. VD3 failed to induce expression of TSLP in human or monkey skin in contrast to mouse, implicating careful extrapolation of this often-used mouse model to AD patients.

Alveolar bone regeneration in response to local application of calcitriol in vitamin D deficient rats.

Vitamin D deficiency is considered to diminish bone regeneration. Yet, raising the serum levels takes months. A topic application of the active vitamin D metabolite, calcitriol, may be an effective approach. Thus, it becomes important to know the effect of vitamin D deficiency and local application on alveolar bone regeneration. Sixty rats were divided into three groups; two vitamin depletion groups and a control group. Identical single defects (2mm diameter) were created in the maxilla and mandible treated with calcitriol soaked collagen in one deficiency group while in the other two groups not. Histomorphometric analysis and micro CTs were performed after 1 and 3weeks. Serum levels of 25(OH)D3 and PTH were determined. Bone formation rate significantly increased within the observation period in all groups. Bone regeneration was higher in the maxilla than in the mandible. However, bone regeneration was lower in the control group compared to vitamin depletion groups, with no significant effects by local administration of calcitriol (micro CT mandible p=0.003, maxilla p<0.001; histomorphometry maxilla p=0.035, mandible p=0.18). Vitamin D deficiency not necessarily impairs bone regeneration in the rat jaw and a single local calcitriol application does not enhance healing.

Vitamin D3 metabolite calcidiol primes human dendritic cells to promote the development of immunomodulatory IL-10-producing T cells

Vitamin D is recognized as a potent immunosuppressive drug. The suppressive effects of vitamin D are attributed to its physiologically active metabolite 1,25 dihydroxy vitamin D3 (calcitriol), which was shown, to prime dendritic cells (DCs) to promote the development of regulatory T (Treg) cells. Despite the potential benefit in treating autoimmune diseases, clinical application of calcitriol is hindered by deleterious side effects manifested by hypercalcemia and hypercalciuria. Conversely, the physiological precursors of calcitriol, vitamin D3 (cholecalciferol) and its first metabolite 25-hydroxy vitamin D3 (calcidiol) are widely applied in the clinic due to their low calcimic burden. However, the mechanisms by which cholecalciferol and calcidiol may modulate adaptive immunity remain elusive. This prompted us to unravel the immunosuppressive capacity of these precursors by assessing their influence on DC functions and the subsequent polarization of naïve CD4+ T cells. In this study we show that, whereas cholecalciferol has insignificant effects on DC maturation and cytokine production, it only weakly primed DCs to induce suppressive T cells. However, like calcitriol, calcidiol not only exerted an inhibitory effect on DC maturation and cytokine production, and primed DCs to promote the development of suppressive IL-10-producing Treg cells. Strikingly, in contrast to the population of IL-10-producing Treg cells induced by calcitriol-primed DCs, the IL-10-producing Treg cells induced by calcidiol-primed DCs exhibited sustained IFN-γ production in face of their suppressive capacity. Experiments with the steroid synthesis inhibitor ketoconazole indicated that the immunomodulatory features of the precursors are dependent on their conversion into calcitriol. Collectively, calcidiol is a potent immune modulator, which may be more adequate than calcitriol for the treatment of chronic inflammatory diseases, since it is less hypercalcimic. This may be of particular interest for the treatment of allergic disease, where concurrent suppression and sustained IFN-γ production by Treg cells effectively counterbalance the Th2-dominated immune responses.

Effects of vitamin D3 derivative – calcitriol on pharmacological reactivity of aortic rings in a rodent PCOS model

BackgroundThe aim of this study was to examine the effects of the hyperandrogenic state in dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS), the vascular responses to different vasoactive agents, and the modulatory role of vitamin D3. MethodsAPCOS model was induced by DHT application in 20 femaleWistar rats. Ten of the DHT treated rats simultaneously received calcitriol treatment. After 10 weeks, myographs were used to test the reactivity of isolated thoracic aortic rings to norepinephrine and acetylcholine. Thereafter, the vascular rings were incubated with the NO-synthase blocker (nitro-L-arginine methyl ester) or the cyclooxygenase inhibitor (indomethacin) for 20min, and the effects of norepinephrine and acetylcholine were re-evaluated. ResultsNorepinephrine-induced vasoconstriction was enhanced after DHT treatment, but this effect was attenuated by calcitriol administration. Vasorelaxation of DHT-treated thoracic aortic rings was impaired, but this could be partly reversed by calcitriol application. Impaired NO-dependent vasorelaxation in DHT-treated animals was mostly reversed by concomitant calcitriol administration, but this effect was diminished by prostanoid-dependent vasoconstriction. ConclusionsThese studies show that the enhanced sensitivity to vasoconstrictors and impaired NO-dependent vasorelaxation in hyperandrogenic PCOS rats could be partially reversed by calcitriol treatment.

Vitamin D metabolism

Irradiation of human skin with ultraviolet B (280-320 nm) initiates the photochemical conversion of 7-dehydrocholesterol via previtamin D3 to vitamin D3. Vitamin D3 needs for its activation two hydroxylation steps in the liver and kidney. The final product, hormonally active 1alpha,25-dihydroxyvitamin D3 (calcitriol), arrives via the circulation to its target tissues and acts in a genomic or nongenomic manner. It has been found that human skin irradiated with ultraviolet B also is able to produce calcitriol in substantial amounts. This cutaneous vitamin D3 pathway is unique and, most likely, of considerable relevance for healthy and diseased skin. It is well known that topical application of calcitriol and its analogs can improve hyperproliferative skin diseases. Some studies have convincingly demonstrated that calcitriol and other vitamin D analogs may also be used for the treatment of immunological, inflammatory, and infectious skin diseases. More recently, it has been found that calcitriol or vitamin D analogs have photoprotective effects and can reduce UV-induced deoxyribonucleic acid damage.

Calcitriol 3 μg/g Ointment: A New Topical Treatment for Psoriasis

Vitamin D receptor modulators have been used extensively for years in the treatment of psoriasis. These agents have demonstrated comparable efficacy to mid-potency corticosteroids and have a good safety profile. Vitamin D receptor modulators are useful as single agents and when used in combination, rotational or sequential therapy with other psoriasis treatments. Calcitriol ointment (1α,25-dihydroxyvitamin D3), the naturally occurring, endogenous, biologically active metabolite of vitamin D3, has recently been approved in the United States as the only Vitamin D3 ointment (Vectical™) available for the topical treatment of psoriasis. Two randomized, double-blind, placebo-controlled clinical trials demonstrated the application of calcitriol 3 μg/g ointment twice daily for eight weeks produced significantly greater improvement than did vehicle ointment on physician-rated and patient-rated scores of global psoriasis severity and improvement in psoriasis symptoms from baseline. Long-term clinical trials have demonstrated that twice-daily calcitriol was safe and well-tolerated for one year or longer and that calcium homeostasis was not significantly affected by continuous treatment up to 52 weeks. A direct comparison of calcitriol and calcipotriol [calcipotriene (Dovonex®)] in patients with chronic plaque psoriasis found that the two agents produced generally similar improvements in psoriasis severity but that calcitriol was associated with fewer cutaneous adverse events. A second comparative study that examined calcitriol and calcipotriene for the treatment of psoriasis in sensitive areas found that calcitriol produced significantly less perilesional edema, erythema and stinging/burning than did calcipotriene. Several clinical trials also support calcitriol as part of combination therapy. Topical calcitriol ointment is a new, safe, effective and well-tolerated treatment that offers considerable flexibility in psoriasis care.

Neuroprotection by co-treatment and post-treating with calcitriol following the ischemic and excitotoxic insult in vivo and in vitro

Several in vivo and in vitro studies have demonstrated the neuroprotective potential of pretreatment with 1α,25-dihydroxyvitamin D3 (calcitriol). The aim of the present study was to determine the effectiveness of calcitriol administered in vivo after a brain ischemic episode in the rat model of perinatal asphyxia, or when co-applied with or without delay during 24-h exposure of mouse hippocampal, neocortical and cerebellar neuronal cultures to glutamate on their 7th and 12th day in vitro (7 DIV and 12 DIV, respectively). Calcitriol was also administered after acute exposure of rat cerebellar neurons to glutamate.In 7-day-old rat pups subjected to hypoxia–ischemia, acute application of calcitriol in a single dose of 2μg/kg, 30min after termination of the insult, or subchronic, 7-day post-treatment with calcitriol, effectively reduced brain damage. The level of neuroprotection exceeded that achieved by hypoxic preconditioning used as the reference neuroprotective method. The results of in vitro experiments revealed the ability of calcitriol to reduce excitotoxicity in a manner dependent on the origin of the neuronal cells, their stage of maturation in culture and the duration of exposure to the excitotoxic insult before calcitriol application. Calcitriol was neuroprotective when it was administered together with glutamate or even after a delay of up to 6h during 24-h excitotoxic challenge of hippocampal and neocortical, but not cerebellar neuronal cultures. Application of calcitriol to cultured cerebellar granule neurons after acute exposure to glutamate was ineffective. In 12 DIV hippocampal cell cultures, 50nM calcitriol inhibited glutamate-induced caspase-3 activity, while only 100nM concentrations were effective in 7 DIV cultures. We ascribe the protective effects of calcitriol to the rapid modulation of mechanisms that are instrumental in the direct anti-apoptotic, neuroprotective action of this compound.

Role of the vitamin D3 pathway in healthy and diseased skin – facts, contradictions and hypotheses

Irradiation of human keratinocytes with UVB (280-320 nm) in vitro and in vivo activates the metabolism of 7-dehydrocholesterol to hormonally active calcitriol. The production of calcitriol in the skin strongly depends on the photosynthesis of vitamin D(3) which is biologically inactive in the first instance. Vitamin D(3) serves as the starting substrate for two subsequent enzymatic hydroxylation steps in epidermal keratinocytes. Both the amount of vitamin D(3) and the activity of anabolic and catabolic vitamin D hydroxylases determine the cutaneous level of calcitriol. The hormonally active metabolite of vitamin D(3) regulates a huge number of genes in keratinocytes, and thus acts in an autocrine and/or paracrine manner. This local pathway of vitamin D(3) is unique, but its relevance for healthy and diseased skin is widely unknown, yet. Experimental findings implicate several questions: (1) Is UVB-induced formation of calcitriol involved in regulation of growth and differentaition of epidermal cells as well as immunological and skin protective processes? (2) What endogenous and exogenous factors including drugs affect the cutaneous vitamin D(3) pathway? From a therapeutical point of view, it has been known for a long time that topical application of calcitriol and its analogs can improve hyperproliferative skin diseases like psoriasis. In spite of many encouraging studies in recent years, the fields of the routinely therapeutical application of calcitriol or vitamin D analogs in dermatology (e.g. treatment of immunological, inflammatory, malignancies and infectious skin diseases) have not been intensified. Why is that?

The Efficacy, Safety and Tolerance of Calcitriol 3 μg/g Ointment in the Treatment of Plaque Psoriasis: A Comparison with Short-Contact Dithranol

Objective: A comparison of efficacy, safety and tolerance of a twice-daily application of calcitriol 3 μg/g ointment with dithranol cream. Methods: The study was an 8-week, prospective, randomised, open, parallel-group trial with 114 patients. Subjects received either 3 μg/g calcitriol ointment (twice daily) or 0.25–2% dithranol cream (once daily for 30 min). Results were measured using global improvement, global severity, PASI, quality of life (QOL) and Psoriasis Disability Index scores. Safety was determined from reports of adverse events and blood chemistry analysis. Results: At final assessment, calcitriol and dithranol were comparably efficacious. Skin irritation was reported by 5% of calcitriol and 72% of dithranol patients. Patients rated QOL and overall acceptability of calcitriol more highly. Conclusions: Twice-daily calcitriol ointment (3 μg/g) is equally effective as a once-daily, short-contact dithranol regimen. However, calcitriol is better tolerated than dithranol, and provides a better QOL and a greater patient acceptability.

Expression of integrin subunits and CD44 isoforms in psoriatic skin and effects of topical calcitriol application.

Increasing evidence suggests involvement of integrins and CD44 isoforms in the pathogenesis of psoriasis, contributing to uncontrolled keratinocyte proliferation, neovascularization, and invasion of inflammatory cells. We have analyzed immunohistochemically in situ expression of integrins (CD29, CDw49b, CDw49c, CDw49e, CDw49f) and CD44 isoforms (CD44 standard, CD44 var/v6, CD44 v10) on frozen sections of normal and psoriatic skin (nonlesional skin, lesional skin before and along with topical calcitriol treatment). We did not observe visual changes of immunoreactivity in normal as compared to nonlesional psoriatic skin, while the staining pattern of CDw49c, CDw49f, and CD29 was severely altered in untreated lesional psoriatic skin. Most markedly, CDw49c, CDw49f, and CD29 were focally upregulated in suprapapillar epidermal compartments of lesional psoriatic skin, a staining pattern that is in accordance with the phenomenon that was described by Pinkus as "squirting papilla". Additionally, an increased proportion of inflammatory and endothelial cells revealed immunoreactivity for CD44(std.) in untreated lesional psoriatic as compared to nonlesional psoriatic or normal skin. After 8 weeks of topical calcitriol treatment (15 micrograms/g ointment), the staining pattern for CDw49c, CDw49f and CD29 was markedly changed in epidermis of lesional psoriatic skin, reverting to the staining pattern characteristic for the nonlesional psoriatic or normal human skin, although epidermal expression of CDw49f was still upregulated and CDw49e-, CDw49f-, CD29-, and CD44(std.)-immunoreactive inflammatory and endothelial cells were still to be found in the dermal compartment.

Topical application of calcitriol alters expression of filaggrin but not keratin K1 in mouse epidermis.

Calcitriol (1 alpha,25-dihydroxyvitamin D3) and its analogues are antiproliferative agents which promote epidermal differentiation in vitro, possibly reflecting their modes of action in the treatment of psoriasis. We examined the effect of calcitriol on early and late terminal differentiation in mouse epidermis in vivo using an immunofluorescence assay to detect keratin K1 and filaggrin expression. Pulse labelling with the tymidine analogue 5-bromo-2-deoxyuridine (BrdUrd) was performed by intraperitoneal injection of mice immediately or 16 h after a single topical application of 0.72 nmol calcitriol. The BrdUrd labelling index (LI) and keratin K1 or filaggrin expression of postmitotic cell cohorts were scored by paired immunofluorescence staining for up to 72 h after BrdUrd labelling. Calcitriol induced cell proliferation as shown by a 100% increase in the BrdUrd LI 17 h after application. The onset of keratin K1 expression in the postmitotic period was, however, unchanged in both series after calcitriol treatment. Filaggrin expression appeared earlier after calcitriol treatment than in control epidermis, probably reflecting altered cell kinetics with increased epidermal turnover. The results suggest that calcitriol only influences the later stages of the keratinocyte differentiation programme, possibly secondarily to its hyperproliferative effect.