Thyroid hormones crosstalk with growth factors: Old facts and new hypotheses

Nongenomic effects of thyroid hormones typically start at the cell surface and do not primarily involve the classical nuclear receptors, but rather a plasma membrane receptor site identified about ten years ago on the integrin αvβ3. Transduction of the thyroid hormone signal from this integrin receptor involves activation of the MAPK pathway and may lead to events such as angiogenesis or tumor cell proliferation. This review focuses on the interaction of thyroid hormones with growth factors, in fact the integrin αvβ3 has been reported to a be a co-receptor for several growth factors such as EGF, IGF-1 and the FGF family, but also for small molecules like resveratrol. Binding of the ligand to integrin αvβ3 is inhibited by tetrac, a metabolite of L-thyroxine, and by its nanoparticulate formulation nanotetrac. Recent microarray studies on tumor cells have shown that tetrac has antiinflammatory effects that are mediated by integrin αvβ3, and tetrac can downregulate the expression of several interleukin genes. Crosstalk between thyroid hormones and vascular growth factors is important for cell migration, vascular calcification and the angiogenic process. Thyroid hormones also show pleiotropic effects on osteoblast function and differentiation, as well as in early pregnancy. The importance of thyroid hormone interaction with neurotrophins and interleukins has also been examined. With integrin αvβ3 firmly established as the plasma membrane receptor future studies will focus on the crosstalk between thyroid hormones and growth factors in order to verify the efficiency of new pharmacological tools, such as nanotetrac.