Thyroid hormones and bone

Allain, TJ; McGregor, A. M.

doi:10.1677/joe.0.1390009

Cited by 129 publications

(87 citation statements)

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“…Thyroid hormones are essential for development and maintenance of the skeleton (Mosekilde et al 1990, Allain & McGregor 1993 and regulate multiple bone cell functions (Klaushofer et al 1995). The main non-collagenous protein of the bone matrix is osteocalcin (OCN).…”

Section: Introductionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 inhibits thyroid hormone-induced osteocalcin expression in mouse osteoblast-like cells via a thyroid hormone response element

Varga

Spitzer²,

Rumpler³

et al. 2003

Journal of Molecular Endocrinology

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Thyroid hormones are important regulators of bone development and metabolism. We have demonstrated that tri-iodothyronine (T3) increased and 1,25-dihydroxyvitamin D3 (1,25D3) attenuated the T3-stimulated expression of osteocalcin (OCN) in the osteoblast-like cell line MC3T3-E1. By means of transfection of promoter-reporter gene constructs we investigated the basal and the regulated transcription of this gene by both hormones. We found that a 0·67 kbp and a 1·3 kbp fragment of the mouse OCN OG2 promoter containing two Runx2 binding sites were significantly more active than a smaller fragment containing only one Runx2 binding site. The longer promoter fragments showed a higher reporter gene expression when the transfected cells were treated with 10 −7 M T3. This expression was attenuated by 1,25D3 dose-dependently. These fragments contain a sequence homologue to the recently identified binding site for the 1,25D3 receptor (VDR) in the rat OCN promoter. Deletion of a part of the promoter containing this VDR response element-like sequence (VDRE) resulted in a higher basal expression but abrogated the regulation by T3 and 1,25D3. Electrophoretic mobility shift assays revealed that the deleted sequence was able to bind both in vitro-translated chicken thyroid hormone receptor (TR) and proteins from nuclear extracts that reacted with an antiserum against TR. From these data we conclude that the VDRE-like sequence of the OG2 promoter contains a thyroid hormone response element.

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Section: Introductionmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 inhibits thyroid hormone-induced osteocalcin expression in mouse osteoblast-like cells via a thyroid hormone response element

Varga

Spitzer²,

Rumpler³

et al. 2003

Journal of Molecular Endocrinology

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“…Hypothyroidism impairs skeletal maturation and leads to epiphyseal dysgenesis, resulting in growth retardation and skeletal abnormalities (Allain & McGregor 1993). In adults, thyrotoxicosis is frequently associated with increased bone turnover and decreased bone mass, which is the result of excessive bone resorption relative to formation (Mosekilde & Melsen 1978, Krolner et al 1983.…”

Section: Introductionmentioning

confidence: 99%

Thyroid hormone stimulation of osteocalcin gene expression in ROS 17/2.8 cells is mediated by transcriptional and post-transcriptional mechanisms

Gouveia

Schultz²,

Bianco³

et al. 2001

Journal of Endocrinology

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We investigated the mechanism of thyroid hormone regulation of osteocalcin (OC) gene expression in osteoblast-like cells (ROS 17/2·8). Treatment with triiodothyronine (T 3 ) (10 8 M) increased OC mRNA levels by 3-fold after 24 h and reached a maximum, 5·4-fold, after 48 h. The mRNA levels of other bonespecific genes, alkaline phosphatase and osteopontin, were not affected by T 3 treatment. Interestingly, T 3 induction of OC mRNA varied according to cell density: 4-fold at 1 10 5 cells/dish and 1·5-fold at 40-60 10 5 cells/ dish. The magnitude of OC mRNA induction by T 3 was 40% lower than induction by 1,25 dihydroxyvitamin D 3 (1,25D 3 ) alone, and the combination of T 3 +1,25D 3 did not further stimulate OC mRNA levels. T 3 induction of OC mRNA was not affected by treatment with cycloheximide (10 µg/ml) for 5 h indicating that new protein synthesis is not required for the response. To study the half-life of OC mRNA, ROS 17/2·8 cells were incubated with actinomycin D. The basal half-life of OC mRNA (means ...) was 6·4 0·2 h which was increased significantly with either T 3 or 1,25D 3 treatment to 10·9 0·6 h and 13·5 0·4 h respectively. T 3 modestly up-regulated the rate of OC gene transcription (1·7 0·2-fold) as determined by run-off assay. T 3 did not induce a reporter construct containing the rat OC gene (rOC) 5 -flanking region (to -1750 bp) or the previously described rOC vitamin D response element, when transfected into ROS 17/2·8 cells. In conclusion, T 3 up-regulates the OC mRNA expression in ROS 17/2·8 cells in a dose-, time-and cell confluence-dependent fashion, and does so by transcriptional and posttranscriptional mechanisms. The greater T 3 induction of OC expression in ROS 17/2·8 cells at low cell density is consistent with findings of thyroid hormone action on bone development.

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“…Thyroid hormones are important regulators of bone development and metabolism (Mosekilde et al 1990, Allain & McGregor 1993 and influence osteoblastic growth and differentiation (Kasono et al 1988, Klaushofer et al 1995, Glantschnig et al 1996. Treatment of the osteoblastic cell line, MC3T3-E1, with T 3 induces the expression of osteoblastic markers such as alkaline phosphatase activity and osteocalcin (Kasono et al 1988.…”

Section: Introductionmentioning

confidence: 99%

Tri-iodothyronine inhibits multilayer formation of the osteoblastic cell line, MC3T3-E1, by promoting apoptosis

Varga¹,

Luegmayr²,

Fratzl‐Zelman³

et al. 1999

Journal of Endocrinology

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Cell death through apoptosis is a well-known mechanism for maintaining homoeostasis in many developmental and pathological processes. We have recently presented evidence for the occurrence of apoptosis during the formation of bone-like tissue in vitro. MC3T3-E1 osteoblast-like cells in culture develop features of the osteoblastic phenotype and form many cell layers embedded in extracellular matrix which can mineralise. Tri-iodothyronine (T 3 ), even though it enhances the expression of many osteoblastic features, attenuates the multilayer formation to about two layers. The aim of this study was to investigate how T 3 prevents multilayer formation. MC3T3-E1 cells were seeded at different densities and cultured for up to 2 weeks. Thereafter we analysed proliferation rate and the distribution of the phases of the cell cycle and studied apoptosis. We found that T 3 did not inhibit DNA synthesis. Analysis of the cell cycle phases showed an increase in the number of cells in G0/G1 with increasing cell density, but no significant effect of T 3 treatment was found. Morphological investigations showed apoptotic features in both cell layers and culture supernatants. The cells exhibited typical plasma membrane blebbings, chromatin condensation, DNA fragmentation and phagocytosed apoptotic bodies. T 3 treatment significantly increased the number of apoptotic cells. We conclude from our data that T 3 inhibits multilayer formation of MC3T3-E1 cells by increasing the rate of apoptosis and not by inhibition of proliferation. Because apoptosis is a fundamental regulatory event during bone tissue differentiation, our findings emphasise the importance of thyroid hormones in bone maintenance and development.

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Thyroid hormones and bone

Cited by 129 publications

References 0 publications

1,25-Dihydroxyvitamin D3 inhibits thyroid hormone-induced osteocalcin expression in mouse osteoblast-like cells via a thyroid hormone response element

1,25-Dihydroxyvitamin D3 inhibits thyroid hormone-induced osteocalcin expression in mouse osteoblast-like cells via a thyroid hormone response element

Thyroid hormone stimulation of osteocalcin gene expression in ROS 17/2.8 cells is mediated by transcriptional and post-transcriptional mechanisms

Tri-iodothyronine inhibits multilayer formation of the osteoblastic cell line, MC3T3-E1, by promoting apoptosis

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