Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-57546
Bergmann, C; Akhmetshina, A; Dees, C; Palumbo, K; Zerr, P; Beyer, C; Zwerina, J; Distler, O; Schett, G; Distler, J H W (2011). Inhibition of glycogen synthase kinase 3β induces dermal fibrosis by activation of the canonical Wnt pathway. Annals of the Rheumatic Diseases, 70(12):2191-2198.
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Glycogen synthase kinase 3β (GSK-3) regulates the phosphorylation and subsequent degradation of β-catenin, thereby preventing aberrant activation of the canonical Wnt pathway. A study was undertaken to define the role of GSK-3 in fibroblast activation and in experimental models of systemic sclerosis (SSc).
siRNA and specific inhibitors were used to inhibit GSK-3 in cultured fibroblasts and in mice. Activation of the canonical Wnt signalling was analysed by determining the levels of nuclear β-catenin and by measuring the mRNA levels of the Wnt target gene Axin2. The effects of GSK-3 on the release of collagen were evaluated in human dermal fibroblasts and in the mouse model of bleomycin-induced skin fibrosis in tight-skin-1 (tsk-1) mice.
Targeting GSK-3 potently activated the canonical Wnt pathway in fibroblasts in vitro and in vivo. Inactivation of GSK-3 dose-dependently stimulated the release of collagen from cultured fibroblasts in a β-catenin-dependent manner and further resulted in progressive accumulation of collagen and dermal thickening in mice. Inhibition of GSK-3 aggravated experimental fibrosis in bleomycin-challenged mice and in tsk-1 mice.
Inhibition of GSK-3 activates the canonical Wnt pathway in fibroblasts, stimulates the release of collagen from fibroblasts, exacerbates experimental fibrosis and is sufficient to induce fibrosis. GSK-3 is therefore a key regulator of the canonical Wnt signalling in fibroblasts and inhibition of GSK-3 results in fibroblast activation and increased release of collagen.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine|
|Dewey Decimal Classification:||610 Medicine & health|
|Deposited On:||29 Jan 2012 16:48|
|Last Modified:||13 Jul 2014 06:41|
|Publisher:||BMJ Publishing Group|
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