S.6.1 β-catenin is a central mediator in SSc
Beyer, C. ; Schramm, A. ; Distler, A. ; Dees, C. ; Taketo, M. M. ; de Crombrugghe, B. ; Distler, O. ; Schett, G. ; Distler, J. H. W. ; Dees, C. ; Tomcik, M. ; Palumbo, K. ; Akhmetshina, A. ; Horn, A. ; Zerr, P. ; Distler, O. ; Schett, G. ; Distler, J. H. W. ; Distler, A. ; Palumbo, K. ; Dees, C. ; Bergmann, C. ; Venalis, P. ; Zerr, P. ; Horn, A. ; Beyer, C. ; MacDougald, O. A. ; Distler, O. ; Schett, G. ; Distler, J. H. W. ; Lagares, D. ; Busnadiego, O. ; Garcia-Fernandez, R. ; Kapoor, M. ; Liu, S. ; Carter, D. ; Abraham, D. ; Shi-Wen, X. ; Carreira, P. ; Fontaine, B. ; Shea, B. ; Tager, A. ; Leask, A. ; Lamas, S. ; Rodriguez-Pascual, F.
In: Rheumatology, 2012, vol. 51, p. ii12-ii14
Ajouter à la liste personnelle- Summary
- Background. β-catenin is the central integrator of canonical Wnt signalling. Since recent evidence suggests a central role of Wnts in fibrosis, we examined the β-catenin/Wnt pathway in SSc and focused on the role of β-catenin in fibroblast activation. Methods. We performed qPCR for several Wnt ligands and axin-2 to examine Wnt expression in SSc skin. We further studied protein levels of Wnt-1, -4, -10b and β-catenin by IHC. To establish the effects of β-catenin/Wnt signalling on collagen release, we created mice with fibroblast-specific stabilization of β-catenin (dEx3 β-catenin (wt/fl) × Col1a2; Cre-ER) as well as mice carrying fibroblast-specific deletion of β-catenin [Ctnnb1(fl/fl) × Col1a2; Cre-ER]. Summary of the results. We could demonstrate mRNA overexpression of Wnt-1, -2, -9a, -9b, -10a, -10b and -16 in SSc skin. Wnt-1, -4 and -10b consistently showed strong expression in SSc skin when compared with healthy skin. On protein level, however, Wnt-4 was indistinguishable between SSc patients and healthy controls, whereas Wnt-1 and Wnt-10b protein levels were increased in SSc skin. The overexpression of Wnt-1 and Wnt-10b resulted in a prominent nuclear accumulation of β-catenin in fibroblasts. Finally, increased mRNA levels of the target gene axin-2 confirmed the activation of canonical Wnt signalling. In dEx3 β-catenin (wt/ex) mice, we addressed the consequences of enhanced Wnt signalling and increased accumulation of β-catenin in SSc. We selectively targeted β-catenin in fibroblasts. Cre-activated dEx3 β-catenin (wt/fl) × Col1a2; Cre-ER mice showed massive and spontaneous dermal thickening even 2 weeks after Cre activation. Eight weeks after Cre-activation, skin thickening cumulated at 102.6% (P < 0.001). In line with the dermal thickening, hydroxyproline content and myofibroblast counts showed strong increases. To test the therapeutic potential of targeting β-catenin/Wnt signaling, we created Ctnnb1(fl/fl) x Col1a2;Cre-ER mice to specifically delete β-catenin in fibroblasts. After Cre activation and β-catenin deletion in fibroblasts, mice were challenged with bleomycin subcutaneously for 4 weeks. We found that Cre-activated Ctnnb1(fl/fl) × Col1a2; Cre-ER mice were protected from bleomycin-induced dermal with a reduction of skin thickening by 71% (P < 0.05). Conclusions. We demonstrated a prominent activation of canonical Wnt signalling in SSc with nuclear accumulation of β-catenin in fibroblasts and activation of the target gene axin-2. Our results showed that fibroblast-specific stabilization of β-catenin resulted in enhanced collagen release, whereas deletion of β-catenin potently reduced collagen production. Together, our findings highlight a key role of β-catenin in fibroblast activation and fibrosis. Thus, β-catenin may be promising molecular target for anti-fibrotic therapies