Dissertation•
Expression of type 2 iodothyronine deiodinase in human osteoblast is stimulated by thyrotropin
01 Jan 2005-
About: The article was published on 2005-01-01 and is currently open access. It has received 25 citations till now. The article focuses on the topics: DIO2 & Iodothyronine deiodinase.
Citations
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TL;DR: Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins, indicating relationships between the two trace elements selenium (Se) and iodine and the hormone network.
Abstract: Recent identification of new selenocysteine-containing proteins has revealed relationships between the two trace elements selenium (Se) and iodine and the hormone network. Several selenoproteins participate in the protection of thyrocytes from damage by H(2)O(2) produced for thyroid hormone biosynthesis. Iodothyronine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. The Se content in endocrine tissues (thyroid, adrenals, pituitary, testes, ovary) is higher than in many other organs. Nutritional Se depletion results in retention, whereas Se repletion is followed by a rapid accumulation of Se in endocrine tissues, reproductive organs, and the brain. Selenoproteins such as thioredoxin reductases constitute the link between the Se metabolism and the regulation of transcription by redox sensitive ligand-modulated nuclear hormone receptors. Hormones and growth factors regulate the expression of selenoproteins and, conversely, Se supply modulates hormone actions. Selenoproteins are involved in bone metabolism as well as functions of the endocrine pancreas and adrenal glands. Furthermore, spermatogenesis depends on adequate Se supply, whereas Se excess may impair ovarian function. Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins.
481 citations
Cites background from "Expression of type 2 iodothyronine ..."
...Bone development and differentiation are controlled by thyroid hormones acting via local cell-specific expression of deiodinases and T3 receptors (615, 627, 628)....
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...No 5 -deiodinase activity is found in bone extracts of D2 knockout mice, and both 1,25-(OH)2 vitamin D3 and TSH via its adenylate cyclase-coupled receptor, which is expressed in OB, stimulate D2 activity in OB in vitro (615, 628)....
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TL;DR: Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture, and data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.
Abstract: Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3′-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.
131 citations
Cites background from "Expression of type 2 iodothyronine ..."
...In osteoblasts data are conflicting (16, 18, 24), although specific D2 activity was identified in whole bone and differentiated MC3T3 osteoblastic cells in one study (17)....
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TL;DR: It is believed that measurement of bone mineral density is recommended in postmenopausal women with DTC starting TSH suppressive therapy and should be subsequently regularly measured to enable timely intervention with bone protective agents.
Abstract: Patients with differentiated thyroid carcinoma (DTC) are commonly treated long-term with thyrotropin (TSH)- suppressive thyroxine replacement therapy resolving in a state of subclinical hyperthyroidism. The relationship between subclinical hyperthyroidism and osteoporosis is not clear. In this review, we systematically selected and analyzed 21 studies addressing this issue. Although multiple methodological differences between studies prevented a structured meta-analysis, our data suggest that postmenopausal women with subclinical hyperthyroidism are most at risk, whereas no increased risk was observed in men and premenopausal women. Based on these findings we believe that measurement of bone mineral density is recommended in postmenopausal women with DTC starting TSH suppressive therapy. This should be subsequently regularly measured to enable timely intervention with bone protective agents.
116 citations
Cites background from "Expression of type 2 iodothyronine ..."
...An exciting new development has been the discovery of functional TSH receptors in bone (32;33) because of the implication that effects that traditionally have been attributed to high thyroid hormone levels may be in effect related to low TSH levels....
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TL;DR: Data suggest that T3 availability especially during skeletal development may be limited by D3-mediated catabolism rather than by MCT8 mediated cellular uptake or D2-dependent T3 production.
85 citations
Cites background or result from "Expression of type 2 iodothyronine ..."
...As release of (125)I may result from non-specific degradation of substrate [30], the specificity of D2-like activity identified in osteoblastic cells [51] requires clarification....
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...Previous studies in SaOS2 and NHOst osteoblastic cells have also reported substantial levels (5–6 fmol/mg/min) of 5'-deiodination [51]....
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...This approach contrasts with previous studies [50,51], which relied solely on sensitive detection of (125)I release that can result from non-specific substrate degradation [30]....
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...[51] reported D2-like activity in SaOS-2 osteosarcoma cells and human NHOst cells....
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...However, similar to studies in ATDC5 cells [50], detection of D2-like activity was based solely on the release of (125)I following incubation of cell extracts with radiolabelled T4 or rT3 [51]....
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TL;DR: It is concluded that in this group of patients, serum TSH was related to indicators of bone remodeling independently of thyroid hormone levels, which may point to a functional role of the TSHR in bone in humans.
Abstract: Objective: It has been proposed that TSH has thyroid hormone-independent effects on bone mineral density (BMD) and bone metabolism. This concept is still controversial and has not been studied in human subjects in detail. We addressed this question by studying relationships between serum TSH concentration and indicators of bone turnover, after controlling for triiodothyronine (T3), free thyroxine (FT4), and non-thyroid factors relevant to BMD and bone metabolism. We also studied the contribution of the TSH receptor (TSHR)-Asp727Glu polymorphism to these relationships. Design: We performed a cross-sectional study with 148 patients, who had been thyroidectomized for differentiated thyroid carcinoma. Methods: We measured BMD of the femoral neck and lumbar spine. FT4 ,T 3, TSH, bone-specific alkaline phosphatase, procollagen type 1 aminoterminal propeptide levels, C-cross-linking terminal telopeptide of type I collagen, and urinary N-telopeptide of collagen cross-links were measured. Genotypes of the TSHR-Asp727Glu polymorphism were determined by Taqman assay. Results: We found a significant, inverse correlation between serum TSH levels and indicators of bone turnover, which was independent of serum FT4 and T3 levels as well as other parameters influencing bone metabolism. We found that carriers of the TSHR-Asp727Glu polymorphism had an 8.1% higher femoral neck BMD, which was, however, no longer significant after adjusting for body mass index. Conclusion: We conclude that in this group of patients, serum TSH was related to indicators of bone remodeling independentlyof thyroid hormone levels. This may point to a functional role of the TSHR in bone in humans. Further research into this mechanism needs to be performed.
56 citations
References
More filters
TL;DR: Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins, indicating relationships between the two trace elements selenium (Se) and iodine and the hormone network.
Abstract: Recent identification of new selenocysteine-containing proteins has revealed relationships between the two trace elements selenium (Se) and iodine and the hormone network. Several selenoproteins participate in the protection of thyrocytes from damage by H(2)O(2) produced for thyroid hormone biosynthesis. Iodothyronine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. The Se content in endocrine tissues (thyroid, adrenals, pituitary, testes, ovary) is higher than in many other organs. Nutritional Se depletion results in retention, whereas Se repletion is followed by a rapid accumulation of Se in endocrine tissues, reproductive organs, and the brain. Selenoproteins such as thioredoxin reductases constitute the link between the Se metabolism and the regulation of transcription by redox sensitive ligand-modulated nuclear hormone receptors. Hormones and growth factors regulate the expression of selenoproteins and, conversely, Se supply modulates hormone actions. Selenoproteins are involved in bone metabolism as well as functions of the endocrine pancreas and adrenal glands. Furthermore, spermatogenesis depends on adequate Se supply, whereas Se excess may impair ovarian function. Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins.
481 citations
TL;DR: Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture, and data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.
Abstract: Hypothyroidism and thyrotoxicosis are each associated with an increased risk of fracture. Although thyroxine (T4) is the predominant circulating thyroid hormone, target cell responses are determined by local intracellular availability of the active hormone 3,5,3′-L-triiodothyronine (T3), which is generated from T4 by the type 2 deiodinase enzyme (D2). To investigate the role of locally produced T3 in bone, we characterized mice deficient in D2 (D2KO) in which the serum T3 level is normal. Bones from adult D2KO mice have reduced toughness and are brittle, displaying an increased susceptibility to fracture. This phenotype is characterized by a 50% reduction in bone formation and a generalized increase in skeletal mineralization resulting from a local deficiency of T3 in osteoblasts. These data reveal an essential role for D2 in osteoblasts in the optimization of bone strength and mineralization.
131 citations
TL;DR: It is believed that measurement of bone mineral density is recommended in postmenopausal women with DTC starting TSH suppressive therapy and should be subsequently regularly measured to enable timely intervention with bone protective agents.
Abstract: Patients with differentiated thyroid carcinoma (DTC) are commonly treated long-term with thyrotropin (TSH)- suppressive thyroxine replacement therapy resolving in a state of subclinical hyperthyroidism. The relationship between subclinical hyperthyroidism and osteoporosis is not clear. In this review, we systematically selected and analyzed 21 studies addressing this issue. Although multiple methodological differences between studies prevented a structured meta-analysis, our data suggest that postmenopausal women with subclinical hyperthyroidism are most at risk, whereas no increased risk was observed in men and premenopausal women. Based on these findings we believe that measurement of bone mineral density is recommended in postmenopausal women with DTC starting TSH suppressive therapy. This should be subsequently regularly measured to enable timely intervention with bone protective agents.
116 citations
TL;DR: Low-normal TSH values are associated with high prevalence of vertebral fractures in women with post-menopausal osteoporosis or osteopenia, independently of thyroid hormones, age and BMD.
102 citations
TL;DR: Data suggest that T3 availability especially during skeletal development may be limited by D3-mediated catabolism rather than by MCT8 mediated cellular uptake or D2-dependent T3 production.
85 citations