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Psoriasis (PsO) is a chronic inflammatory skin disease with both local and systemic components. PsO-associated arthritis, known as psoriatic arthritis (PsA), develops in approximately 13%-25% of PsO patients. Various factors associated with both PsO and PsA indicate that these conditions are part of a single disease. Identification of novel targets for the development of drugs to treat both PsO and PsA is desirable to provide more patient-friendly treatment regimens. Such targets will likely represent 'common checkpoints' of inflammation, for example key components or transduction cascades of the signalling pathways involved. Emerging evidence supports involvement of the non-canonical Wnt signalling pathways in the development of both PsO and PsA, especially the Wnt5a-activated signalling cascades. These, together with interlinked factors, are crucial in the interactions among keratinocytes, immune cells and inflammatory factors in PsO, as well as among chondrocytes, osteoblasts and osteoclasts that trigger both subchondral bone remodelling and cartilage catabolism in PsA. This review focuses on the pathological role of Wnt5a signalling and its interaction with other interlinked pathways in both PsO and PsA, and also on the main challenges for future research, particularly with respect to molecules targeting Wnt signalling pathways for the treatment of PsO and PsA., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Psoriasis is a one of the most common chronic skin diseases, which affects 0.6-4.8% of the general population. Amentoflavone (AMF) belongs to the biflavonoid class of flavonoids, possessing various biological effects, such as anti-inflammatory, antioxidant, and anti-apoptotic effects. In the present study, we aimed to investigate the effect of AMF on psoriasis in imiquimod (IMQ) psoriasis-like lesions in mice and keratinocyte proliferation in HaCaT cells. We showed that AMF reduced skinfold thickening, and improved erythema and scaling scores and histological lesions in IMQ-treated mice. AMF exerted potent anti-inflammatory effect via influencing a variety of proinflammatory cytokines, including tumor necrosis factor α, interleukin (IL)-17A, IL-22, and IL-23 in local skin lesions and the whole body. In M5 (a cocktail of cytokines)-treated HaCaT cells, AMF significantly inhibited cell proliferation, promoted apoptosis, and inhibited the increase of expression of cyclin D1, cyclin E, IL-17A, and IL-22. In addition, AMF inhibited the upregulation of p65 NF-κB under psoriatic condition. Moreover, overexpression of p65 NF-κB significantly suppressed the effect of AMF on keratinocyte proliferation, apoptosis, and expression of cyclin D1, cyclin E, IL-17A, and IL-22. These results demonstrated that suppression of NF-κB was involved in AMF-resulted anti-proliferative, apoptosis-promoting, anti-inflammatory effects in keratinocytes. The data demonstrate that AMF may serve as potential therapeutic option for patients with psoriasis.

Background / Aims: Wnt5a is overexpressed in psoriasis lesions, however the mechanism by which Wnt5a is involved in the pathogenesis of psoriasis is not clear. To address this, the expression of Wnt5a in psoriatic lesions and its effect on keratinocyte cell proliferation and apoptosis was examined in vitro., Methods: The expression levels of WNT5A, and genes encoding its receptors frizzled2 (FZD2) and frizzled5 (FZD5) were examined in samples obtained from individuals with psoriasis and healthy controls. Knockdown of Wnt5a with short interfering (si)RNAs was performed in cultured HaCaT keratinocytes and normal human keratinocytes (NHK), and the expression of Wnt5a, protein kinase C (PKC), and β-catenin were determined, and cell cycle activity, proliferation and apoptosis were assessed., Results: The expression of WNT5A, FZD2 and FZD5 mRNA and protein were increased in psoriatic lesions. Wnt5a knockdown suppressed proliferation and induced apoptosis in HaCaT and NHK cells. Additionally, expression of PCNA, MKI67, CCND1, BCL2, CTNNB1, and genes encoding PKC and survivin were downregulated, whereas CASP3 was upregulated. The mRNA levels of the Wnt pathway inhibitors DKK1 and SFRP1 were upregulated, Western blotting analyses demonstrated reduction in β-catenin and PKC protein levels., Conclusion: Knockdown of Wnt5a suppresses the proliferation of keratinocytes and induces apoptosis by inhibiting the Wnt/β-catenin or Wnt5a/Ca(2+) pathways., (© 2015 S. Karger AG, Basel.)

Background/Aims: Wnt5a is overexpressed in psoriasis lesions, however the mechanism by which Wnt5a is involved in the pathogenesis of psoriasis is not clear. To address this, the expression of Wnt5a in psoriatic lesions and its effect on keratinocyte cell proliferation and apoptosis was examined in vitro. Methods: The expression levels of WNT5A, and genes encoding its receptors frizzled2 (FZD2) and frizzled5 (FZD5) were examined in samples obtained from individuals with psoriasis and healthy controls. Knockdown of Wnt5a with short interfering (si)RNAs was performed in cultured HaCaT keratinocytes and normal human keratinocytes (NHK), and the expression of Wnt5a, protein kinase C (PKC), and β-catenin were determined, and cell cycle activity, proliferation and apoptosis were assessed. Results: The expression of WNT5A, FZD2 and FZD5 mRNA and protein were increased in psoriatic lesions. Wnt5a knockdown suppressed proliferation and induced apoptosis in HaCaT and NHK cells. Additionally, expression of PCNA, MKI67, CCND1, BCL2, CTNNB1, and genes encoding PKC and survivin were downregulated, whereas CASP3 was upregulated. The mRNA levels of the Wnt pathway inhibitors DKK1 and SFRP1 were upregulated, Western blotting analyses demonstrated reduction in β-catenin and PKC protein levels. Conclusion: Knockdown of Wnt5a suppresses the proliferation of keratinocytes and induces apoptosis by inhibiting the Wnt/β- catenin or Wnt5a/Ca2+ pathways. [ABSTRACT FROM AUTHOR]