The role of new pro-inflammatory and/or pro-fibrotic molecules in the pathogenesis of systemic sclerosis


Authors: M. Tomčík
Authors‘ workplace: 1. lékařská fakulta Univerzity Karlovy v Praze
Published in: Čes. Revmatol., 22, 2014, No. 3, p. 127-142.
Category: The summary of the dissertation

Overview

Introduction:
Systemic sclerosis (SSc) is a generalized connective tissue disease affecting the skin and internal organs. The pathogenesis of SSc is characterized by inflammation, vasculopathy and fibrosis. To date, none of the tested drugs have demonstrated convincing efficacy in the treatment of SSc. S100A4 is involved in the regulation of cell motility, proliferation, apoptosis, angiogenesis and remodeling of the extracellular matrix. It was originally described as a promoter of metastasis in tumors, however, its pro-inflammatory properties have recently been demonstrated in inflammatory rheumatic diseases. The aim of this study was to assess the role of S100A4 in pathological activation of fibroblasts in SSc and in experimental models of dermal fibrosis.

Results:
The expression of S100A4 was increased in the skin of SSc patients, in SSc fibroblasts and in experimental fibrosis in a TGF-ß / Smad dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, inhibition of S100A4 or its complete deficit abrogated the pro-fibrotic effects of TGF-ß and decreased the release of collagen. S100A4 knock-out mice (S100A4-/-) were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower counts of activated fibroblasts, so called myofibroblasts. Similarly, deficiency of S100A4 also ameliorated fibrosis in the Tight skin-1 (Tsk-1) mouse model. Anti-fibrotic effects of the inactivation of S100A4 in both experimental models of dermal fibrosis were mediated by inhibition of TGF-ß / Smad signaling.

Conclusion:
Our results characterize S100A4 as a positive regulator of the stimmulatory effects of TGF-ß on fibroblasts in SSc. S100A4 is induced by TGF-ß and in turn amplifies the stimulatory effects of canonical TGF-ß / Smad signaling on collagen synthesis by SSc fibroblasts and on induction of fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-ß and neutralizing antibodies against S100A4 are currently evaluated in tumors, S100A4 might become a candidate molecule for novel anti-fibrotic therapies.

Key words:
S100A4, fibrosis, scleroderma, Smad3, fibroblasts


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Labels
Dermatology & STDs Paediatric rheumatology Rheumatology
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