Hypothyroidism and Thyroxine-Induced Hyperthyroidism Differentially Affect Cathepsins, Mct8, and Thyroid Tissue Architecture in Male Mice

Adequate thyroid hormone concentrations are essential for tissue homeostasis, including in the thyroid gland. Thyrocyte function is regulated by the hypothalamic–pituitary–thyroid axis and by the coordinated action of thyroglobulin-processing cathepsins and thyroid hormone transporters such as monocarboxylate transporter 8 (Mct8). Here, we investigated the effects of hypothyroidism and thyroxine-induced exogenous hyperthyroidism on thyroid proteases and Mct8 expression in male mice. Thyroid follicular architecture was largely preserved in hyperthyroidism, whereas hypothyroidism resulted in increased thyrocyte extensions, collapsed follicular lumina, and enhanced thyroglobulin turnover. Cathepsin B was reduced in both conditions, pro-cathepsin D declined only in hyperthyroidism, and cathepsin L was upregulated in hypothyroidism. Consistently, thyroglobulin fragments were approximately two-fold more abundant in hypothyroid tissue. Mct8 expression remained unchanged in hyperthyroidism but was nearly absent in hypothyroidism. Hypothyroid tissue also exhibited markedly increased thyrocyte proliferation, while cell death rates were not altered across thyroid dysfunction. In addition, alterations in laminin indicated disbalanced extracellular matrix remodeling in hypothyroidism. Together, these findings demonstrate profound changes in thyroid architecture, proteolytic activity, and thyroid hormone transport under chronic thyroid dysfunction, particularly hypothyroidism. Further studies are needed to define the specific role of individual proteases in these processes.