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20-04-2006 | Thyroid | Article

Role of D2 in TSH control unraveled

Abstract

Free abstract

Harvard University researchers believe they may have finally resolved a longstanding paradox relating to a thyroid enzyme and its role in the thyroxine (T4)-mediated thyroid stimulating hormone (TSH) negative-feedback mechanism.

T4 is a prohormone and must be converted to triiodothyronine (T3) to become biologically active. Type 2 idiothyronine deododinase (D2) is believed to play a role in this mechanism, but, counterintuitively, D2 activity is rapidly lost in the presence of T4.

In an attempt to unravel the details of this pathway, Marcelo Christoffolete and co-workers studied adult Sprague-Dawley rats. They found that pituitary thyrotroph cells expressed both D2 and TSH, and that D2 expression was increased in rats in which hypothyroidism was induced by the addition of methimazole and sodium perchlorate to their drinking water.

Next, the team studied two mouse thyrotroph-derived cells: TtT-97, a transplantable thyrotrophic tumor, and TαT1, an immortalized SV40 antigen-expressing pituitary cell line.

Both cells had increased D2 expression and were sensitive to negative regulation by T3-induced proteasomal degradation of D2. Despite this, expression of the Dio2 gene in TαT1 cells was higher than their T4-induced D2 "ubiquitinating capacity."

Accordingly, D2 activity and overall T3 production in these cells were sustained even at T4 concentrations many times above those within the physiological range.

"In this system, free T4 concentrations and net D2-mediated T3 production correlated negatively with TSHβ gene expression," the authors conclude.

"These results resolve the apparent paradox between the homeostatic regulation of D2 and its role in mediating the critical mechanism by which T4 triggers the TSH negative feedback."