Role of caveolin-1 in thyroid phenotype, cell homeostasis, and hormone synthesis: in vivo study of caveolin-1 knockout mice.

In the human thyroid, caveolin-1 is localized at the apex of thyrocytes, but its role there remains unknown. Using immunohistochemistry, (127)I imaging, transmission electron microscopy, immunogold electron microscopy and quantification of H2O2, we found that in caveolin-1 knockout mice the thyroid cell homeostasis was disrupted, with evidences of oxidative stress, cell damage and apoptosis. An even more striking phenotype was the absence of thyroglobulin and iodine in half of the follicular lumina and their presence in the cytosol, suggesting that the iodide organification and binding to thyroglobulin were intracellular rather than at the interface apical membrane/extracellular colloid. The later abnormality may be secondary to the observed mislocalization of the thyroid hormone synthesis machinery (dual oxidases, thyroperoxidase) in the cytosol. Nevertheless, the overall uptake of radioiodide, its organification and secretion as thyroid hormones were comparable to those of wild type mice, suggesting adequate compensation by the normal TSH retro-control. Accordingly, the levels of free T4 and TSH were normal. Only the levels of free T3 showed a slight decrease in caveolin-1 knockout mice. However, when the TSH levels were increased through low iodine chow and sodium perchlorate, the induced goiter was more prominent in caveolin-1 knockout mice. We conclude that caveolin-1 plays a role in proper thyroid hormone synthesis as well as in cell number homeostasis. Our study demonstrates for the first time a physiological function of caveolin-1 in the thyroid gland. Because the expression and subcellular localization of caveolin-1 were similar between the normal human and murine thyroids, our findings in the caveolin-1 knockout mice may have direct relevance to the human counterpart. Key words: thyroid, Duox, caveolin-1, iodination.