Thyroid hormones regulate skeletal development, acquisition of peak bone mass and adult bone maintenance. Abnormal thyroid status during childhood disrupts bone maturation and linear growth, while in ...adulthood it results in altered bone remodeling and an increased risk of fracture
This review considers the cellular effects and molecular mechanisms of thyroid hormone action in the skeleton. Human clinical and population data are discussed in relation to the skeletal phenotypes of a series of genetically modified mouse models of disrupted thyroid hormone signaling.
Euthyroid status is essential for normal bone development and maintenance. Major thyroid hormone actions in skeletal cells are mediated by thyroid hormone receptor α (TRα) and result in anabolic responses during growth and development but catabolic effects in adulthood. These homeostatic responses to thyroid hormone are locally regulated in individual skeletal cell types by the relative activities of the type 2 and 3 iodothyronine deiodinases, which control the supply of the active thyroid hormone 3,5,3’-L-triiodothyronine (T3) to its receptor.
Population studies indicate that both thyroid hormone deficiency and excess are associated with an increased risk of fracture. Understanding the cellular and molecular basis of T3 action in skeletal cells will lead to the identification of new targets to regulate bone turnover and mineralization in the prevention and treatment of osteoporosis. This article is part of a Special Issue entitled Thyroid hormone signaling.
► Thyroid hormones regulate bone development, peak bone mass and adult bone turnover. ► Thyroid hormone deficiency and excess are associated with increased fracture risk. ► Euthyroid status is essential for normal bone development and maintenance. ► TRα mediates the major actions of T3 in the skeleton. ► T3 exerts anabolic effects during growth but catabolic action in the adult skeleton.
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The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) and TRβ mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the ...“His-Phe switch” to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound 16g, which is a potent TRβ agonist (EC50: 21.0 nM, 85.0% of the maximum efficacy of 1) with outstanding selectivity for TRβ over TRα and also effectively activates the TRβH435R mutant. Then, we developed a highly efficient synthetic method for 16g. Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation. 16g also showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively, 16g is a well-characterized selective and mutation-sensitive TRβ agonist for further investigating its function in treating dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH).
The effects of thyroid hormones (THs) on brain development and function are largely mediated by the control of gene expression. This is achieved by the binding of the genomically active T3 to ...transcriptionally active nuclear TH receptors (TRs). T3 and the TRs can either induce or repress transcription. In hypothyroidism, the reduction of T3 lowers the expression of a set of genes, the positively regulated genes, and increases the expression of negatively regulated genes. Two mechanisms may account for the effect of hypothyroidism on genes regulated directly by T3: first, the loss of T3 signaling and TR transactivation, and second, an intrinsic activity of the unliganded TRs directly responsible for repression of positive genes and enhancement of negative genes. To analyze the contribution of the TR subtypes α and β, we have measured by RT-PCR the expression of a set of positive and negative genes in the cerebral cortex and the striatum of TR-knockout male and female mice. The results indicate that TRα1 exerts a predominant but not exclusive role in the regulation of positive and negative genes. However, a fraction of the genes analyzed are not or only mildly affected by the total absence of TRs. Furthermore, hypothyroidism has a mild effect on these genes in the absence of TRα1, in agreement with a role of unliganded TRα1 in the effects of hypothyroidism.
Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a ...critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we identified a novel nuclear localization signal in the A/B domain of thyroid hormone receptor α1 that is absent in thyroid hormone receptor β1 and inactive in the oncoprotein v-ErbA. Our prior studies showed that thyroid hormone receptor α1 exits the nucleus through two pathways, one dependent on the export factor CRM1 and the other CRM1-independent. Here, we identified three novel CRM1-independent nuclear export signal (NES) motifs in the ligand-binding domain as follows: a highly conserved NES in helix 12 (NES-H12) and two additional NES sequences spanning helix 3 and helix 6, respectively. Mutations predicted to disrupt the α-helical structure resulted in a significant decrease in NES-H12 activity. The high degree of conservation of helix 12 suggests that this region may function as a key NES in other nuclear receptors. Furthermore, our mutagenesis studies on NES-H12 suggest that altered shuttling of thyroid hormone receptor β1 may be a contributing factor in resistance to thyroid hormone syndrome. Taken together, our findings provide a detailed mechanistic understanding of the multiple signals that work together to regulate TR shuttling and transcriptional activity, and they provide important insights into nuclear receptor function in general.
Background: Thyroid hormone receptor (TR) shuttles between the cytosol and nucleus and regulates gene expression in response to hormone.
Results: TR shuttling is mediated by multiple, transferable nuclear localization and nuclear export signals.
Conclusion: Functional domains of TR work in concert to modulate shuttling.
Significance: Molecular characterization of signals that regulate shuttling is crucial for understanding nuclear receptor function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Silkworms are economically important insects that have the ability to produce large amounts of silk. They have mass breeding methods and silk glands, which are specialized tissues that secrete silk ...fibroin and sericin. Thus, the production of recombinant proteins in a transgenic silkworm system is a promising approach. We developed a silkworm, Bombyx mori, as a host expression insect for recombinant proteins and successfully produced different proteins including antibodies, glycoproteins, and membrane receptors. The thyroid hormone receptor (TR) is a regulatory factor for many physiological phenomena. It is a lipophilic protein that has DNA-binding and ligand-binding domains. Based on our previous experiences, it was inferred that the recombinant TR easily formed aggregates and precipitates which is potentially due to an unstructured hinge domain. We applied the silkworm expression system to produce mice TRβ1 that was fused with glutathione S-transferase. Using 160 larvae, the yield of the recombinant GST-TRβ was approximately 4 mg, and the purified GST-TRβ completely retained its physiological activity. Our results indicated that the recombinant TRβ was secreted extracellularly using the silk fibroin signal peptide sequence. Moreover, we found that the expression system of silkworms was applicable to nuclear proteins.
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•We purified a functional thyroid hormone receptor, a type of nuclear protein, using the transgenic silkworm secretory expression.•The purified recombinant thyroid hormone receptor showed a specific DNA binding activity.•A poly-brominated biphenyl compound partially inhibited the DNA binding activity of the thyroid hormone receptor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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A Mutation in the Thyroid Hormone Receptor Alpha Gene Bochukova, Elena; Schoenmakers, Nadia; Schoenmakers, Erik ...
New England journal of medicine/The New England journal of medicine,
01/2012, Volume:
366, Issue:
3
Journal Article
Peer reviewed
Open access
On whole-exome sequencing, a child with clinical hypothyroidism but borderline-abnormal thyroid hormone levels was found to have a heterozygous nonsense mutation in THRα, encoding a mutant protein ...inhibiting wild-type receptor action in a dominant negative manner.
Thyroid hormones have diverse actions, which include regulation of skeletal growth, maturation of the central nervous system, cardiac and gastrointestinal function, and energy homeostasis. In addition, thyroid hormones control their own production by feedback inhibition of hypothalamic thyrotropin-releasing hormone and pituitary thyroid-stimulating hormone, which direct their synthesis or release. These physiological effects are principally mediated by hormone action through nuclear receptor proteins that act as ligand-inducible transcription factors and either positively or negatively regulate the expression of target genes in different tissues in a hormone-dependent manner.
The receptors are encoded by two genes (
THRA
and
THRB
), each of . . .
Cigarette smoke contains over 4800 compounds, including at least 200 toxicants or endocrine disruptors. Currently, effects of cigarette smoke on thyroid hormone (TH) levels remains to be clarified. ...Here, we demonstrate that cigarette smoke extract (CSE) possesses thyroid hormone properties and acts synergistically as a partial agonist for thyroid hormone receptors (TRs) in the presence of TH. In transient gene expression experiments, CSE stimulated transcriptional activity with TH in a dose-dependent manner. Stimulatory effects were observed with physiological TH concentrations, although CSE did not activate TRs without TH. CSE (5%) dissolved in phosphate-buffered saline (PBS) supplemented with 1 nM TH was approximately comparable to 3.2±0.1 and 2.3±0.2 nM of TRα1 and TRβ1, respectively. To illustrate probable mechanisms of the CSE agonistic activity, effects on TR mediated transcriptional functions with cofactors were investigated. With a mammalian two-hybrid assay, CSE recruited the nuclear coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC1) to the TR. Unsaturated carbonyl compounds, acrolein, crotonaldehyde, and methyl vinyl ketone, representative constituents of CSE, retained such agonistic properties and possibly contributed to stimulatory effects. The results suggest that CSE recruits a transcriptional activator and may reinforce TH binding to the TR additively, resulting in gene expression. CSE partially agonizes TH action and may disturb the function of various nuclear hormone receptor types and their cofactors to disrupt the physiological processes.
Gonadotropin hormones and their receptors play a central role in the control of male and female reproduction. In recent years, there has been growing evidence surrounding the complexity of ...gonadotropin hormone/receptor signaling, with it increasingly apparent that the Gαs/cAMP/PKA pathway is not the sole signaling pathway that confers their biological actions. Here we review recent literature on the different receptor–receptor, receptor–scaffold, and receptor–signaling molecule complexes formed and how these modulate and direct gonadotropin hormone-dependent intracellular signal activation. We will touch upon the more controversial issue of extragonadal expression of FSHR and the differential signal pathways activated in these tissues, and lastly, highlight the open questions surrounding the role these gonadotropin hormone receptor complexes and how this will shape future research directions. Summary sentence Gonadotropin hormone receptors are essential for reproduction. Here we describe the molecular aspects of how gonadotropin hormones direct intracellular signaling and physiological responses via receptor-receptor and receptor-signalosome interactions.
Glioma is one of the most common types of primary intracranial tumors. The relationship between triiodothyronine (T3) and glioma is not clear. This study aimed to investigate the effect of T3 on the ...proliferation of glioma cells and its mechanism. Cell viability was analyzed by cell counting kit 8 assay. Flow cytometry analysis was used to detect cell apoptosis and cell cycle. Thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) were silenced by transfecting si-THRA and si-THRB plasmids into HS683 and A172 glioma cells. Western blot was performed to assess the protein expressions. The results indicated that triiodothyronine (T3) affected the viability, apoptosis and cell cycle of HS683 and A172 glioma cells. Cell apoptosis was significantly inhibited in si-THRA and si-THRB experimental groups. Moreover, knockdown of THRA and THRB reversed the G1 and G2 phase arrest led by T3 and induced an up-regulation of cyclin D1 expression. The phosphorylated extracellular signal-regulated kinase (p-ERK), p-AKT, and phosphorylated signal transducer and activator of transcription (p-STAT3) proteins were markedly increased by inhibiting THRA and THRB in HS683 and A172 glioma cells. T3 affected apoptosis and cell cycle of glioma cells through regulating THRA and THRB expressions. THRA and THRB may affect glioma development through regulating, at least partially, the mitogen-activated protein kinase (MAPK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways.
Abstract Background Thyroid hormones are essential for the maintenance of pregnancy and a deficiency in maternal thyroid hormones has been associated with early pregnancy losses. The aim of this ...study was a systematic investigation of the influence of mifepristone (RU 486) on the expression of the thyroid hormone receptor (THR) isoforms THRα1, THRα2, THRβ1 and THRβ2 on protein and mRNA-level. Methods Samples of placental tissue were obtained from patients with mifepristone induced termination of pregnancy ( n = 13) or mechanical induced termination of normal pregnancy ( n = 20), each from the 4th to 13th week of pregnancy. Expression of THRα1, THRα2, THRβ1 and THRβ2 was analysed on protein level by immunohistochemistry and on mRNA level by real time RT-PCR (TaqMan). The influence of progesterone on THR gene expression was analysed in the trophoblast tumour cell line BeWo by real time RT-PCR (TaqMan). Results Nuclear expression of THRα1, THRα2 and THRβ1 is downregulated on protein level in mifepristone (RU 486) treated villous trophoblast tissue. In decidual tissue, we found a significant downregulation only for THRα1 in mifepristone treated tissue. On mRNA level, we also found a significantly reduced expression of THRA but no significant downregulation for THRB in placental tissue. The gene THRA encodes the isoform THRα and the gene THRB encodes the isoform THRβ. The majority of cells expressing the thyroid hormone receptors in the decidua are decidual stromal cells. In addition, in vitro experiments with trophoblast tumour cells showed that progesterone significantly induced THRA but not THRB expression. Conclusions Termination of pregnancy with mifepristone (RU 486) leads to a downregulation of THRα1, THRα2 and THRβ1 in villous trophoblasts and in addition to a decreased expression of THRA in placental tissue. Decreased expression of THRα1 induced by RU486 could also be found in the decidua. Therefore inhibition of the progesterone receptor may be responsible for this downregulation. This assumption is supported by the finding, that stimulation of the progesterone receptor by progesterone itself up-regulated THRA in trophoblast cells in vitro.
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