Initial characterization of the thyroid stimulating hormone receptor knock-out mouse: The TSH receptor...it's not just for thyroids anymore.

摘要

The thyrotropin receptor (TSHR) is a member of the heterotrimeric G-protein coupled family of receptors whose main function is to regulate thyroid hormone synthesis and production. Outside of the thyroid gland, the TSHR is expressed in many tissues, such as adipose tissue, brain, heart, pituitary, bone, kidney, testis, and thymus, although the function of the TSHR in these tissues remains an enigma. In this study we generated a TSHR-null (TSHR-KO) mouse by homologous recombination (gene knock-out) to use as a model system for the study of TSHR function in the thyroid and non-thyroidal tissues. As expected, the TSHR-KO was profoundly hypothyroid, with no detectable thyroid hormone and dramatically elevated TSH. The TSHR-KO failed to accumulate iodide in the thyroid, as the protein responsible for that action, the sodium-iodide symporter, was absent from their thyroid. A thyroid hormone replacement regimen was developed to render the mice euthyroid, which would allow us to discern between phenotypes directly attributable to the TSHR-null mutation from those of hypothyroidism, expanding the utility of the model from studying the already well characterized impact of the TSHR on thyroid physiology to studying the relatively unknown physiology of other TSHR-expressing tissues. To that end, changes in adipose tissue morphology were discovered, leading to overall changes in body composition. The TSHR also appeared to be important in bone biology, as the TSHR-KO presented with abnormal bone histology, increased numbers of osteoblast and osteoclast precursors, and decreased bone mineral density. This initial study demonstrated that the TSHR-KO mouse should be an excellent system in which to study TSHR function in non-thyroidal tissues.