Type 3 iodothyronine deiodinase (D3) is the major physiologic inactivator of thyroid hormone. This selenoenzyme, previously identified in human placenta and brain, catalyzes the inner-ring deiodination of T(4) to reverse T(3) and T(3) to 3, 3'-diiodothyronine, both of which are biologically inactive. We analyzed D3 expression in several human adult and fetal tissues by immunohistochemistry and correlated the results with D3 activity assays where possible. High D3 expression was present in the placental syncytiotrophoblasts and cytotrophoblasts, endothelium of fetal vessels, and maternal decidua. D3 was also present at other sites of maternal-fetal interface, including the umbilical arteries and vein and the fetal respiratory, digestive, and urinary tract epithelium. Surprisingly, D3 was also present in the endometrial glands of nonpregnant human uteri, and endometrial activity approximated that of term placenta. The presence of D3 at maternal-fetal interfaces is consistent with its role in modulating the thyroid status of the human fetus and its expression in endometrium suggests that local regulation of thyroid status is important in implantation.

The active thyroid hormone 3,5,3′ triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. Conversely, the expression of T3-dependent genes was reduced and after injury regeneration markedly delayed in muscles of mice null for the gene encoding D2 (Dio2), despite normal circulating T3 concentrations. Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3. In conclusion, the FoxO3/D2 pathway selectively enhances intracellular active thyroid hormone concentrations in muscle, providing a striking example of how a circulating hormone can be tissue-specifically activated to influence development locally.