Deiodination and Cellular Proliferation: Parallels between Development, Differentiation, Tumorigenesis, and Now Regeneration

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, this morphogenic event is disrupted in tadpoles treated with iopanoic acid, a competitive inhibitor of D3 catalytic activity (4). D3 expression has also been associated with changes in the proliferation of undifferentiated mammalian cells, illustrated by a recent report that isolated brown adipocyte precursor cells express high D3 mRNA and activity during proliferation (5). Although D3 is highly expressed in developing organs, its activity falls precipitously upon birth. With the exception of the central nervous system and a few other tissues that share the feature of rapidly proliferating progenitor cells, such as the uterine endometrium (6) and the follicles of the skin (7), D3 is undetectable in most mature tissues, including the liver (8). However, outside of normal physiology, D3’s robust reactivation has been documented in a number of disease states, including tumorigenesis and critical illness (9,10,11,12). Clinical studies document that this induction of inner-ring deiodination is sufficient to impact systemic thyroid status in certain patients (9,13). Whether there are functional consequences of D3 reactivation to the tissue microenvironment is a somewhat separate question, and this has become an area of intense investigation in recent years. As demonstrated by the recent discovery by Dentice et al. (14) that D2 inhibition in the developing growth plate increases chondrocyte proliferation via induction of PTHrP, deiodination is a potent mechanism to modulate thyroid status in a tissue- or even cell-specific manner. A novel connection between D3 and tumor cell proliferation was recently revealed by a study of basal cell carcinoma where D3 was shown to promote the proliferation of malignant keratinocytes by inhibiting the action of circulating thyroid hormone. Keratinocytes that expressed D3 had higher rates of proliferation as measured by cyclin D1 expression and thymidine uptake. This finding was also confirmed in vivo using a nude mouse model to show that basal carcinoma cells that were depleted of endogenous D3 had much slower tumor growth (7). In addition to D3’s expression in embryonic tissues and tumors, animal studies show that D3 can also be reactivated in response to diverse tissue injuries, which include myocardial infarction (15), hypertrophic cardiac failure (16,17), chronic inflammation (18,19), and neural injury (20). As in fetal development, this D3 expression can induce local hypothyroidism and inhibit thyroid hormone-dependent transcriptional activity in an anatomically specific manner (16). Given the diverse effects of thyroid hormone in different tissues, it is reasonable to suspect that D3 induction is functionally significant in the pathophysiology of certain injuries. Consistent with this, one early study implicated D3 in the process of regeneration by showing that sciatic nerve cryolesion in rats is followed by sustained D3 expression in the distal nerve segment that persists until functional recovery is complete (20). This is finding is now supported and extended in the current study by Kester et al. (2). The paper by Kester et al. (2) in this issue of Endocrinology shows the robust induction of D3 activity in partial hepatectomy, a classic model of tissue regeneration. This is associated with a severalfold decrease in serum and tissue thyroid hormone concentrations, demonstrating D3’s ability to impact both systemic and local thyroid status. D3 activity correlated with hepatocyte bromodeoxyuridine incorporation, providing novel quantitative evidence to support the hypothesis that D3 promotes cell proliferation. Although the specific molecular mechanism of D3’s induction in this system was not identified, an increase in D3 mRNA was documented by RT-PCR. The current paper provides novel in vivo evidence that supports an important role of D3-induced hypothyroidism in the tissue response to injury, and further study of this regeneration model holds the potential to reveal broader implications to wound healing. Although more research is needed to elucidate the physiological consequences of D3 expression to the function of various tissues, the current findings of Kester et al. (2) indicate that deiodination influences cellular proliferation in several diverse settings that include embryogenesis, tumorigenesis, and now tissue regeneration. As proposed by the authors, further studies using a genetic approach and a conditional D3 knockout animal are indicated as a means to irrefutably prove D3’s functional role and gain insight into the effects of thyroid hormone in tissue injury.