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Vitamin D and A derivatives are well-known endogenous substances responsible for skin homeostasis. In this study we topically treated shaved mouse skin with a vitamin D agonist (MC903) or vitamin D antagonist/partial agonist (ZK159222) and compared the changes with acetone (control treatment) treatment for 14 days. Topical treatment with ZK159222 resulted in increased expression of genes involved in retinoic acid synthesis, increased retinoic acid concentrations and increased expression of retinoid target genes. Clustering the altered genes revealed that heparin-binding epidermal growth factor-like growth factor, the main driver of epidermal hyperproliferation, was increased via RARγ-mediated pathways, while other clusters of genes were mainly decreased which were comparable to the changes seen upon activation of the RARα-mediated pathways. In summary, we conclude that epidermal hyperproliferation of mouse skin in response to a topically administered vitamin D receptor antagonist/partial agonist (ZK159222) is induced via increased retinoic acid synthesis, retinoic acid levels and increased RARγ-mediated pathways. [ABSTRACT FROM AUTHOR]

Background: Omalizumab, a humanized recombinant monoclonal anti‐IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment‐refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double‐blind, placebo‐controlled study. Methods: Chronic spontaneous urticaria patients (18‐75 years) were randomized to either 300 mg omalizumab (n = 20) or placebo (n = 10) administered s.c. every 4 weeks for 12 weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG‐U133Plus2.0 microarrays. Statistical analyses were performed using R packages. Results: At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two‐thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P < 0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes ≥16). Conclusion: Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab‐mediated clinical improvement observed in patients with CSU. The gene expression of the lesional skin of patients with chronic spontaneous urticaria shows a distinct signature when compared to their nonlesional skin and the skin of healthy volunteers. The pattern of gene expression in the lesional skin of omalizumab‐treated patients are different than before treatment, but not in their nonlesional skin. In treatment responders, omalizumab treatment shows reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/healthy volunteer expression levels consistent with observed clinical improvement. [ABSTRACT FROM AUTHOR]

Retinoid-X receptor (RXR)- and retinoic acid receptor (RAR)-mediated signaling is induced by retinoic acids (RA), which are involved in the regulation of skin permeability, differentiation and immune response. Dysregulation of retinoid signaling is present in various skin disorders. Topically and systemically administered synthetic RAR or RXR agonists might influence retinoid-mediated signaling in the skin of RARE reporter animals and gene expression analysis for retinoid, skin homeostasis and skin inflammation marker genes and local retinoid concentrations. Mice were treated orally and topically with synthetic ligands and bioimaging, QRT-PCR and retinoid analysis were performed. Topical application of the synthetic RAR ligand AM580 significantly enhanced retinoid signaling in skin while topical application of the RXR ligand LG268 did not influence retinoic acid receptor re-sponse elements (RARE)-mediated signaling. Systemic treatments with LG268 decreased the expression of genes involved in skin homeostasis, RA synthesis and skin RA concentrations, while it increased various markers for skin inflammation and RA degradation, which corresponds to decreased skin RARE signaling. We conclude from these observations that increased systemic concentrations of an RXR -ligand may be one reason for reduced retinoid signaling, -reduced all-trans RA levels in the skin, reduced epidermal homeostasis and increased skin inflammation marker expression with potential relevance for various skin disorders, like atopic dermatitis. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]