Pathogenesis of Multinodular Goiter in Elderly XB130-Deficient Mice: Alteration of Thyroperoxidase Affinity with Iodide and Hydrogen Peroxide

Background: Multinodular goiter (MNG) is the most common disorder of the thyroid gland. Aging and genetic mutations that impair thyroid hormone (TH) production have been implicated in the development of MNG. XB130 is an adaptor/scaffold protein predominantly expressed in the thyroid gland. XB130 deficiency leads to transient postnatal growth retardation in mice due to congenital hypothyroidism. We studied the formation of MNG and possible mechanisms in elderly mice.Methods: Thyroid glands of male and female Xb130-knockout (Xb130(-/-)), heterozygous (Xb130(+/-)), and wild-type (Xb130(+/+)) mice at the ages of 12-20 months were harvested for visual examination, histopathological, and immunohistological analyses. Blood and thyroid samples were collected after feeding elderly mice with a low iodine diet for I-125 uptake and perchlorate discharge assay. The activity of thyroperoxidase (Tpo) was examined by spectrophotometric evaluation of iodide oxidation.Results: While moderate MNG was seen in Xb130(+/+) and Xb130(+/-) mice, severe MNG, characterized by multiple nodules intermixed with dilated colloid-rich macrofollicles, was found only in Xb130(-/-) mice at 18 months. Thyrocyte cytoskeletal structure and cell adhesion molecules were disorganized, and TH production was significantly reduced. Reduced iodide organification was seen in elderly Xb130(+/+) mice and further enhanced in Xb130(-/-) mice. In Xb130(+/+) mice, Tpo shows high affinity with hydrogen peroxide (H2O2) throughout aging, but reduced affinity with iodide in an age-dependent manner. By contrast, in elderly Xb130(-/-) mice, the affinity of Tpo for iodide remained high, but the affinity of Tpo for H2O2 was reduced.Conclusions: The pathophysiological features in the thyroid glands of aged Xb130(-/-) mice closely resemble the features of MNG in humans. Moderate MNG in elderly mice was dramatically aggravated by XB130 deficiency. Reduced affinity of Tpo for H2O2 may contribute to MNG development via oxidative stress. This could be specific to XB130 deficiency but also could be a common mechanism in MNG. Its clinical relevance should be further investigated.