Thyroid function and effect of aging in combined hetero/homozygous mice deficient in thyroid hormone receptors alpha and beta genes

Abstract

The maintenance of thyroid hormone (TH) homeostasis is dependent on the synthesis and secretion of TH regulated by TSH. This is achieved, in turn, by the negative feedback of TH on TSH secretion and synthesis, which requires the interaction with TH receptors (TRs). Derived by alternative splicing of two gene transcription products, three TRs (TR 1, TR 2 and TR 1) interact with TH while another, TR 2, binds to DNA but not to TH. In this study we compare the results of thyroid function tests in mice with deletions of the TR and TR genes alone and present novel data on mice that are double homozygous and combined heterozygous. Homozygous deletions of both the TR and TR in the same mouse (TR o/o; TR / ) resulted in serum TSH values only slightly lower than those in athyreotic, Pax8 knockout mice. Whereas the absence of TR alone does not cause resistance to TH, the absence of TR in the presence of TR results in a 205, 169, 544% increase in serum thyroxine (T 4 ), triiodothyronine (T 3 ) and TSH concentrations respectively. However, in the absence of TR , loss of one TR allele can worsen the resistance to TH with a 243 and 307% increase in T 4 and T 3 respectively. Similarly, while the heterozygous mouse with a single TR allele shows no alteration in thyroid function, the concomitant deletion of TR brings about mild but significant resistance to TH. Furthermore, the severity of the resistance to TH was noted to decrease with age in parallel with the decrease in serum free T 4 values also seen in wild-type mice. These results demonstrate that (1) unliganded TR or TR are not absolutely necessary for the upregulation of TSH; (2) TR but not TR is sufficient for TH-mediated downregulation of TSH; and (3) TR may partially substitute for TR in mediating a partial TH-dependent TSH suppression.

Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action

“…In addition, it has also been reported by our laboratory and others that absence of TR␤ does not cause such a decline in basal heart rates and, in fact, results in a slight increase in heart rate attributed to increased circulating levels of TH in these mice (Table 3) (15,19,20,33,35,36). However, there appear to be a number of differences in baseline heart rates of WT mice dependent on strain, even in papers by the same laboratories.…”

Thyroid hormone-stimulated differentiation of primary rib chondrocytes in vitro requires thyroid hormone receptor β

“…These mice have disorganized chondrocyte columns and reduced width of the hypertrophic zone. However, they also have mild hypothyroxinemia (Macchia et al 2001, Weiss et al 2002, raising the possibility that the observed phenotype results from reduced local TH availability.…”

Do unliganded thyroid hormone receptors have physiological functions?

“…One can conclude that, in physiological conditions, most of the TRs (95%) are liganded in thyrotrope cells. The production of TSH in Pax8 / mice, which have very low TH concentrations and are deeply hypothyroid, is twice that in TR double-knockout mice (Weiss et al 2002a), suggesting that TRs exert aporeceptor activity in these cells. Remarkably, TR 1 but not TR seems to be responsible for aporeceptormediated activation of TSH (Sadow et al 2002).…”