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• W2128592257 abstract "Psoriasis is a chronic inflammatory skin disease believed to be mediated by T lymphocytes, dendritic cells and Langerhans cells 1. Striking alterations in epidermal growth and differentiation result in hyperkeratosis and scales in psoriatic patients. Furthermore, vascular hyperplasia is observed in psoriasis. Therefore, cell-mediated immunity, epidermal growth and differentiation and vascular hyperplasia are all regarded to play important roles in the pathomechanisms of psoriasis. To understand further the pathomechanisms of psoriasis, multiple transgenic mice have been established, which develop human ‘psoriasis-like’ symptoms 2, 3. As shown in Table 1, multiple transgenic mice show phenotypes resembling human psoriasis by overexpressing cytokine and related proteins (IL-1α, IL-6, IL-17C, IL-20, IFN-γ, p40, STAT3, TGF-β1, TNF-α), RAS and related proteins (MEK1, Raf, RAS), angiogenesis-related proteins (amphiregulin, Tie2, VEGF) and other proteins (BMP-6, heparanase, integrins, PPARβ/δ). antibodies against some of these factors are now in therapeutic use for human psoriasis). Wnt5a is one of the molecules suggested to be implicated in the pathogenesis of human psoriasis. The Wnt signalling pathways direct growth and morphogenesis during development and continue to regulate cell proliferation and differentiation throughout the adult life. There are two major Wnt signalling pathways, the canonical Wnt/βcatenin and the non-canonical Wnt/Ca2+ pathway 4. Microarray analysis comparing the RNA expression profiles between the uninvolved and lesional skin of psoriasis revealed that 179 genes were more than twofold differentially expressed in the lesional skin 4. The list included 16 genes with known or possible association to the canonical Wnt/β-catenin or the non-canonical Wnt/Ca2+ pathway. The expression of Wnt5a was fourfold higher in lesional skins. Other Wnt molecules were largely unchanged (Wnt4 and Wnt16), or tended to be expressed at lower levels (Wnt7b). Moreover, Wnt5a lowers the concentration of interferon (IFN) required to induce target genes and increases the magnitude of IFN target gene induction, suggesting a molecular mechanism underlying IFN hypersensitivity in psoriasis by Wnt5a 5. WNT5a transcripts were induced by IL-1α, tumour necrosis factor (TNF)-α, IFN-γ and transforming growth factor-α in cultured keratinocytes 6. Frizzled 2 (FZD2) and FZD5, which encode receptors for Wnt5A, were also increased in lesional psoriatic skin. In contrast, expression of WIF1 mRNA, encoding a secreted antagonist of the Wnt proteins, was downregulated >10-fold in lesional skin, along with decreased WNT inhibitory factor (WIF)-1 immunostaining. Taken together, those data suggested non-canonical Wnt/Ca2+ pathways driven by interactions between Wnt-5a and its cognate receptors play a role in the pathomechanism of psoriasis. Based upon the hypothesis, Zhu et al. 7 generated transgenic mice with epidermal Wnt5a overexpression under the control of the human K14 promoter to establish psoriasis model mice. Contrary to their initial expectations, the skin of Wnt5a transgenic mice appeared normal and showed no visible features of psoriasis, including inflamed hyperkeratotic plaques. Moreover, the differentiation and proliferation of transgenic epidermis showed no obvious difference to wild-type skin, as indicated by the normal expression of basal K14, granular K10 and cornified loricrin. Several reasons might underlie the dissociation between the observation in human psoriasis and the normal appearance of Wnt5a transgenic epidermis. Both epidermal differentiation and the skin immune systems differ widely between human and mouse skin. Therefore, K14-promoter-driven Wnt5a overexpression may not affect cutaneous T lymphocytes and/or dendritic cells in murine skin, which are believed to be indispensable for the pathogenesis of human psoriasis 1. Expression of receptors or inhibitors for Wnt5a was not studied in the transgenic mice. Wnt5a receptor expression in murine epidermis might not be strong enough to respond to the increased Wnt5a and to develop phenotypes in the epidermis of transgenic mice. However, Wnt5a transgenic mice displayed impaired hair follicle transition from telogen to anagen. Multiple transgenic or knockout mice with overexpression or deficiency in Wnt and Wnt-related genes developed abnormalities in hair follicle morphogenesis and/or cycling 8. Indeed, Wnt5a is highly expressed in hair follicle dermal papilla cells and attenuates Wnt3a-mediated elevated β-catenin signals, including induction of Axin2, EP2 and LEF1 expression in dermal papilla cells 9. In Wnt5a transgenic mice, Wnt5a overproduced in hair matrix may act on dermal papilla cells by downmodulating canonical Wnt signalling pathway 10 and controls hair follicle cycling. Further precise comparisons between Wnt5a-deficient mice and wild-type control mice are necessary for the argument whether Wnt5a plays a role in the hair follicle morphogenesis. As to the clinical application of Wnt5a and Wnt5a inhibitors, the current study showed that they are more likely to be applicable for alopecia or hypertrichosis rather than for psoriasis. However, further clinical studies are necessary to prove their usefulness for human hair disorders. DO, TY, SH, RK, MY, DN and MN wrote the manuscript. The authors declare no conflicting interest." @default.
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• W2128592257 date "2015-02-26" @default.
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• W2128592257 title "Is Wnt5a overexpression sufficient for generating a psoriasis-like phenotype in transgenic mice?" @default.
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