Thyroid hormone influences gene expression in virtually all vertebrate tissues. Thyroid hormone signaling results from the interaction of T4 or T3 with nuclear receptors that, in concert with other transcription factors, stimulate or repress the expression of target genes. The activity of this signaling pathway depends upon ligand availability and is sensitive to changes in serum thyroid hormone concentrations that can result from abnormalities in glandular secretion or the peripheral metabolism of circulating iodothyronines. In addition to such factors that impact thyroid status systemically, thyroid hormone signaling is also modulated locally in the tissue microenvironment by ligand activation and inactivation (1). In this issue of Endocrinology, Kester et al.(2) show that hepatocytes express the thyroid hormone-inactivating enzyme type 3 deiodinase (D3) during liver regeneration and provide novel in vivo evidence that D3-mediated local hypothyroidism promotes cellular proliferation after tissue injury.

D3 is one of three enzymes that comprise the iodothyronine deiodinase family of selenoenzymes. D1 and D2 catalyze the activation of the T4 prohormone into T3 via outer-ring deiodination. In contrast, D3 catalyzes the inactivation of both T4 and T3 via inner-ring deiodination. All three deiodinases work in concert to maintain thyroid hormone homeostasis in the euthyroid state. In addition, primary changes in deiodinase expression can induce downstream changes in thyroid hormone signaling. This latter concept is well established in embryonic development, where the coordinated expression of D2 and D3 permits the precise control of local thyroid hormone concentrations in an anatomically and temporally specific manner (3). A direct relationship between D3 and cellular proliferation was initially defined by studies in the developing Xenopus laevis retina, where D3 expression in the dorsal ciliary marginal zone inhibits thyroid hormone-dependent proliferation and facilitates the asymmetric retinal growth required for the normal transition to binocular vision. Demonstrating D3’s functional relevance,