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

Abstract

In 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 H(2)O(2), we found that in caveolin-1 knockout mice thyroid cell homeostasis was disrupted, with evidence of oxidative stress, cell damage, and apoptosis. An even more striking phenotype was the absence of thyroglobulin and iodine in one-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 apical membrane/extracellular colloid interface. The latter 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 retrocontrol. Accordingly, the levels of free thyroxine and TSH were normal. Only the levels of free triiodothyronine showed a slight decrease in caveolin-1 knockout mice. However, when 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 normal human and murine thyroids, our findings in caveolin-1 knockout mice may have direct relevance to the human counterpart.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Sections were rinsed in running tap water, dehydrated, cleared, and mounted. Reproduced with permission from Senou et al (20).…”

“…SIMS is the most sensitive surface analysis technique, with elemental detection limits ranging from parts per million to parts per billion. It is uniquely suited for the study of trace ions distribution at the ultrastructural level (20).…”

“…The identification of lumina devoid of 127 I and/or the demonstration of significant amounts of 127 I in the cytoplasm of the epithelial cells or on the apical membrane indicates impairment of the iodination pathway. To define the ultrastructural distribution of iodide using SIMS, thyroid lobes are processed in a similar way as for electron microscopy, including fixation with glutaraldehyde and preparation of semithin sections (20).…”

“…127 I is homogeneously distributed in the follicular lumina and in a few intracytoplasmic vesicles. Reproduced with permission from Senou et al (20).…”

“…Fine subcellular distribution studies can be done with IHC and confocal microscopy; immunogold staining electron microscopy allows detection of antigens at very high resolution in studies of subcellular distribution ( Fig. 5) (20,27). …”