Avouac, J; Palumbo, K; Tomcik, M; Zerr, P; Dees, C; Horn, A; Maurer, B; Akhmetshina, A; Beyer, C; Sadowski, A; Schneider, H; Shiozawa, S; Distler, O; Schett, G; Allanore, Y; Distler, J H W (2012). Inhibition of AP-1 signaling abrogates TGF-ß mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis and Rheumatism, 64(5):1642-1652.
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PURPOSE: To investigate whether c-Jun and c-Fos contribute to the pathologic activation of fibroblasts in systemic sclerosis (SSc) and evaluate the anti-fibrotic potential of selective AP-1 inhibition. METHODS: Expression of c-Jun and c-Fos was determined by real-time PCR and immunohistochemistry. Fibroblasts were stimulated with TGF-β and incubated with T-5224, a small-molecule inhibitor of AP-1 or transfected with small interfering RNA duplexes against c-Jun and c-Fos. Collagen synthesis was quantified by real-time PCR and hydroxyproline assay. Differentiation of resting fibroblasts into myofibroblasts was assessed by staining for α-smooth muscle actin and stress fibers. The anti-fibrotic potential of T-5224 was evaluated in mouse models of dermal fibrosis induced by bleomycin or by adenoviral overexpression of a constitutively active TGF-ß receptor type I. RESULTS: Upregulation of c-Jun and c-Fos was detected in animal models of SSc and the skin and dermal fibroblasts of SSc patients. Stimulation of healthy fibroblasts with TGFβ induced the expression of c-Jun and c-Fos. T-5224 or nucleofection with SiRNA directed against c-Jun and c-Fos abrogated the profibrotic effects of TGF-β. T-5224 decreased the release of collagen selectively in SSc fibroblasts. T-5224 was well tolerated and prevented dermal fibrosis induced by bleomycin or adenoviral activation of TGF-β signaling. CONCLUSION: AP-1 specify is upregulated in a TGF-β dependent manner in SSc. The selective AP-1 inhibitor T-5224 reduced collagen synthesis selectively in SSc fibroblasts and efficiently prevented the development of experimental dermal fibrosis. Thus, AP-1 might be a promising new molecular target for the treatment of SSc.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine|
|DDC:||610 Medicine & health|
|Deposited On:||29 Jan 2012 17:44|
|Last Modified:||23 Nov 2012 15:06|
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