Objectives Pathologic fibroblast activation drives fibrosis of the skin and internal organs in patients with systemic sclerosis (SSc). β-catenin is an integral part of adherens junctions and a central component of canonical Wnt signaling. Here, the authors addressed the role of β-catenin in fibroblasts for the development of SSc dermal fibrosis. Methods Nuclear accumulation of β-catenin in fibroblasts was assessed by triple staining for β-catenin, prolyl-4-hydroxylase-β and 4′,6-diamidino-2-phenylindole (DAPI). The expression of Wnt proteins in the skin was analysed by real-time PCR and immunohistochemistry. Mice with fibroblast-specific stabilisation or fibroblast-specific depletion were used to evaluate the role of β-catenin in fibrosis. Results The auhors found significantly increased nuclear levels of β-catenin in fibroblasts in SSc skin compared to fibroblasts in the skin of healthy individuals. The accumulation of β-catenin resulted from increased expression of Wnt-1 and Wnt-10b in SSc. The authors further showed that the nuclear accumulation of β-catenin has direct implications for the development of fibrosis: Mice with fibroblast-specific stabilisation of β-catenin rapidly developed fibrosis within 2 weeks with dermal thickening, accumulation of collagen and differentiation of resting fibroblasts into myofibroblasts. By contrast, fibroblast-specific deletion of β-catenin significantly reduced bleomycin-induced dermal fibrosis. Conclusions The present study findings identify β-catenin as a key player of fibroblast activation and tissue fibrosis in SSc. Although further translational studies are necessary to test the efficacy and tolerability of β-catenin/Wnt inhibition in SSc, the present findings may have clinical implications, because selective inhibitors of β-catenin/Wnt signaling have recently entered clinical trials.

Background and objectivesFibrosis is a major socioeconomic burden, but effective antifibrotic therapies are not available in the clinical routine. There is growing evidence for a central role of Wnt signalling in fibrotic diseases such as systemic sclerosis, and we therefore evaluated the translational potential of pharmacological Wnt inhibition in experimental dermal fibrosis.MethodsWe examined the antifibrotic effects of PKF118-310 and ICG-001, two novel inhibitors of downstream canonical Wnt signalling, in the models of prevention and treatment of bleomycin-induced dermal fibrosis as well as in experimental dermal fibrosis induced by adenoviral overexpression of a constitutively active transforming growth factor (TGF)-β receptor I.ResultsPKF118-310 and ICG-001 were well tolerated throughout all experiments. Both therapeutic approaches showed antifibrotic effects in preventing and reversing bleomycin-induced dermal fibrosis as measured by skin thickness, hydroxyproline content and myofibroblast counts. PKF118-310 and ICG-001 were effective in inhibiting TGF-β receptor I-driven fibrosis as assessed by the same outcome measures.ConclusionsBlockade of canonical Wnt signalling by PKF118-310 and ICG-001 showed antifibrotic effects in different models of skin fibrosis. Both therapies were well tolerated. Although further experimental evidence for efficacy and tolerability is necessary, inhibition of canonical Wnt signalling is a promising treatment approach for fibrosis.

Preeclampsia, the onset of hypertension and proteinuria during pregnancy, is a common medical disorder with high maternal and fetal mortality and morbidity. The underlying pathology remains poorly understood and includes inflammation, endothelial dysfunction, and an unbalanced thromboxane A2/prostacyclin ratio. For women with systemic lupus erythematosus (SLE), particularly those with preexisting renal disease or with active lupus, the risk of developing preeclampsia is up to 14% higher than it is among healthy individuals. The mechanism is still unknown and the data for preventing preeclampsia in lupus pregnancies are rare. Modulating the impaired thromboxane A2/prostacyclin ratio by administration of low-dose aspirin appears to be the current best option for the prevention of preeclampsia. After providing an overview of the pathogenesis of preeclampsia, preeclampsia in lupus pregnancies, and previous trials for prevention of preeclampsia with aspirin treatment, we recommend low-dose aspirin administration for all lupus patients starting prior to 16 weeks of gestation. Patients with SLE and antiphospholipid syndrome should receive treatment with heparin and low-dose aspirin during pregnancy.

Background Fibrosis is a major socioeconomic burden, but effective anti-fibrotic therapies are not available in clinical routine. Fibrosis emerges from excessive release of extracellular matrix components by pathologically activated fibroblasts, which results in disruption of the physiological tissue architecture and causes organ failure. Growing evidence demonstrates a crucial role of canonical Wnt signaling in this pathologic fibroblast activation in fibrotic diseases such as systemic sclerosis (SSc). In SSc, overexpression of Wnt1 and Wnt10b leads to stabilization of β-catenin and increased transcription of target genes, resulting in tissue fibrosis. Of note, TGF-β signaling stimulates canonical Wnt signaling by decreasing the levels of the endogenous Wnt inhibitor Dickkopf-1. Objectives To evaluate the translational potential of these recent findings, we tested pharmacological Wnt inhibitors in different experimental models of dermal fibrosis. Methods We evaluated the anti-fibrotic effects of PKF118-310 and ICG-001, two novel inhibitors of downstream canonical Wnt signaling, in the model of bleomycin-induced dermal fibrosis and in experimental fibrosis induced by adenoviral overexpression of a constitutively active TGF-β receptor I (adTBRIact). Antifibrotic effects were assessed by measuring dermal thickness, hydroxyproline content and α-smooth muscle actin counts. Body weight, activity and texture of the fur were used to assess tolerability. Results PKF118-310 and ICG-001 were well-tolerated throughout all experiments with animals showing constant body weight, normal activity and normal texture of the fur. PKF118-310 showed strong anti-fibrotic effects in both the bleomycin and the adTBRIact mouse model. In the bleomycin challenged mice, skin thickness was reduced by 43.5% (p =0.002), and by 63.1% (p = 0.0020) in the adTBRIact model. Hydroxyproline content and α-smooth muscle actin-positive fibroblasts were significantly reduced in a similar extent in both models. Similar to PKF118-310, ICG-001 was effective in inhibiting bleomycin-induced dermal fibrosis and TGF-β receptor I-driven fibrosis. When treated with ICG-001, skin thickening decreased by 49.1% (p <0.0001) in bleomycin-challenged mice. In addition, ICG-001 reduced dermal thickening by 47.7% (p=0.0025) in the adTBRIact model. Similar to the reduction of dermal thickening, hydroxyproline content and α-smooth muscle actin-positive fibroblasts were significantly reduced in both models. Conclusions Blockade of canonical Wnt signaling by PKF118-310 and ICG-001 showed anti-fibrotic effects in the inflammation-dependent model of bleomycin-induced dermal fibrosis and the TGF-β-driven adTBRIact model, reflecting different stages of fibrotic disease. Efficacy of Wnt inhibitors in the adTBRIact model provided further evidence for a close link between TGF-β- and canonical Wnt signaling. Of note, both Wnt inhibitors showed good tolerability in our models. Although further experimental evidence for efficacy and tolerability is necessary, inhibition of canonical...

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