RESUMO
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Key players mediating fibrosis are myofibroblasts (MF) that, following transforming growth factor ß (TGFß) exposure, produce a collagen-rich extracellular matrix (ECM) that induces myofibroblast differentiation. Myofibroblasts express αvß3 integrin (a membrane receptor for thyroid hormones) and miRNA-21 that promotes deiodinase-type-3 expression (D3), causing the degradation of triiodothyronine (T3) that attenuates fibrosis. We hypothesized that αvß3 affects the fibrotic processes through its thyroid hormones (THs) binding site. To test this, dermal fibroblasts (DF) were cultured with/without TGFß and removed with a base, leaving only normal/fibrotic ECMs in wells. Then, DF were cultured on the ECMs with/without tetrac (αvß3 ligand, T4 antagonist), and evaluated for pro-fibrotic characteristics, αvß3, miRNA-21, and D3 levels. Blood free-T3 (fT3), miRNA-21 levels, and the modified Rodnan skin score (MRSS) were evaluated in SSc patients. We found that the "fibrotic-ECM" significantly increased the pro-fibrotic characteristics of DF and the levels of miRNA-21, D3, and αvß3, compared to the "normal-ECM." Tetrac significantly inhibited the effects of the "fibrotic-ECM" on the cells. In accordance with tetrac's effect on D3/miRNA-21, a negative correlation was found between the patients' fT3 to miRNA-21 levels, and to the development of pulmonary arterial hypertension (PAH). We conclude that occupying the THs binding site of αvß3 may delay the development of fibrosis.
