期刊
ARTHRITIS AND RHEUMATISM
卷 64, 期 5, 页码 1642-1652出版社
WILEY
DOI: 10.1002/art.33501
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资金
- Societe Francaise de Rhumatologie
- Groupe Francais de Recherche sur la Sclerodermie (bourse AMPLI)
- Association des Sclerodermiques de France
- ARTICULUM
- Encysive Young Investigator Award
- CMH [00000023728]
- Actelion
- Pfizer
- Ergonex
- Bristol-Myers Squibb
- Sanofi-Aventis
- United BioSource
- Medac
- Swedish Orphan Biovitrum
- Novartis
- Active Biotec
- GlaxoSmithKline
- Celgene
- Bayer
- Roche
Objective To investigate whether c-Jun and c-Fos contribute to the pathologic activation of fibroblasts in systemic sclerosis (SSc) and to evaluate the antifibrotic potential of selective activator protein 1 (AP-1) inhibition. Methods Expression of c-Jun and c-Fos was determined by real-time polymerase chain reaction (PCR) and immunohistochemical analysis. Fibroblasts were stimulated with transforming growth factor beta (TGF beta) and incubated with T-5224, a small-molecule inhibitor of AP-1, or were transfected with small interfering RNA (siRNA) 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 a-smooth muscle actin and stress fibers. The antifibrotic potential of T-5224 was evaluated in mouse models of dermal fibrosis induced by bleomycin or by adenoviral overexpression of a constitutively active TGF beta receptor type I. Results Up-regulation of c-Jun and c-Fos was detected in mouse models of SSc and in the skin and dermal fibroblasts of patients with SSc. Stimulation of healthy fibroblasts with TGF beta induced the expression of c-Jun and c-Fos. Treatment with T-5224 or nucleofection with siRNA directed against c-Jun and c-Fos abrogated the profibrotic effects of TGF beta. T-5224 decreased the release of collagen selectively in SSc fibroblasts. T-5224 was well tolerated and prevented dermal fibrosis induced by bleomycin or by adenoviral activation of TGF beta signaling. Conclusion AP-1 is up-regulated in a TGF beta-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.
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