alpha v beta 3 Integrin as a Link between the Development of Fibrosis and Thyroid Hormones in Systemic Sclerosis

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 beta (TGF beta) exposure, produce a collagen-rich extracellular matrix (ECM) that induces myofibroblast differentiation. Myofibroblasts express alpha v beta 3 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 alpha v beta 3 affects the fibrotic processes through its thyroid hormones (THs) binding site. To test this, dermal fibroblasts (DF) were cultured with/without TGF beta and removed with a base, leaving only normal/fibrotic ECMs in wells. Then, DF were cultured on the ECMs with/without tetrac (alpha v beta 3 ligand, T4 antagonist), and evaluated for pro-fibrotic characteristics, alpha v beta 3, 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 alpha v beta 3, 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 alpha v beta 3 may delay the development of fibrosis.