A Lack of Thyroid Hormones Rather than Excess Thyrotropin Causes Abnormal Skeletal Development in Hypothyroidism

Bassett, J. H. Duncan; Williams, Allan J.; Murphy, Elaine; Boyde, A.; Howell, Peter; Swinhoe, R; Archanco, Marta; Flamant, Frédéric; Samarut, Jacques; Costagliola, Sabine; Vassart, Gilbert; Weiss, Roy E.; Refetoff, Samuel; Williams, Graham R.

doi:10.1210/me.2007-0221

Cited by 108 publications

(86 citation statements)

References 46 publications

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“…Neonatal P1 mice and limbs from animals aged between P21 and P42 should be stained with alizarin red (bone) and alcian blue (cartilage) to investigate intrauterine skeletal development and the progress of postnatal bone formation. Measurement of skull dimensions, fontanelles, and suture areas provide an assessment of intramembranous ossification; measures of bone length and growth plate histomorphometry are accurate and sensitive indicators of the progression of endochondral ossification (725)(726)(727)(728)(729)(730)(731).…”

Section: And Recommendation 66mentioning

confidence: 99%

“…Such parameters in the mouse are at the limits of spatial resolution by micro-CT. Detailed analysis of bone microarchitecture and micromineralization density can be analyzed using specialist back scattered electron-scanning electron microscopy (BSE-SEM) techniques (725)(726)(727)(729)(730)(731). The effects of altered thyroid status on linear growth and bone structural parameters are significant and readily determined using these methods, although specialist equipment and data analysis methods are required.…”

Section: And Recommendation 67mentioning

confidence: 99%

“…Bone resorption is investigated in bone sections stained for TRAcP, and osteoclast numbers and surface determined by light microscopy and normalized to total bone surface. Cortical and trabecular bone resorption surfaces in vivo can also be determined using specialized BSE-SEM techniques (725,727,729), although such methods are not routinely or widely available. Bone formation should be quantified in dual calcein-labeled bone by standard histomorphometry and indices of bone formation determined using ImageJ (http://rsbweb.nih.gov/ij) according to the American Society for Bone and Mineral Research standard system of nomenclature (736).…”

Section: And Recommendation 69amentioning

confidence: 99%

“…Alternative high resolution methods using confocal microscopy can be performed in specialist laboratories (725,737). Gene expression studies can be performed in paraffin-embedded decalcified sections of bone and cartilage (in situ hybridization and IHC), using RNA extracted from tissue samples (mRNA expression and profiling) and in skeletal tissue extracts (protein expression and enzyme activity assays) (726,727,(729)(730)(731)(738)(739)(740). & …”

Section: And Recommendation 69amentioning

confidence: 99%

See 3 more Smart Citations

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Bianco

Anderson

Forrest

et al. 2014

Thyroid

Self Cite

176

106

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Section: And Recommendation 66mentioning

confidence: 99%

Section: And Recommendation 67mentioning

confidence: 99%

Section: And Recommendation 69amentioning

confidence: 99%

Section: And Recommendation 69amentioning

confidence: 99%

See 2 more Smart Citations

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Bianco

Anderson

Forrest

et al. 2014

Thyroid

Self Cite

176

106

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“…However, TSHRs are known to be expressed in multiple extrathyroidal tissues including bone, brain, kidney, testis, and cells of the immune system (15), but the role of TSHR in these tissues is not clear. For example, potential effects of TSHR activation on bone metabolism have been proposed (16,17), but contradictory findings have been reported (18,19) and a definitive conclusion has not been drawn (15). A small-molecule agonist that can be administered orally, diffuses out of the bloodstream easily, and can be produced at low cost may allow for any effect of TSHR activation on bone and the other tissues that express TSHRs to be definitively shown.…”

mentioning

confidence: 99%

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Neumann¹,

Huang

Titus

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

113

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Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.7TMR ͉ G protein-coupled receptor ͉ low-molecular-weight ligands ͉ radioiodide uptake ͉ TSH receptor S mall-molecule agonists and antagonists for 7-transmembrane-spanning receptors (7TMRs; G protein-coupled receptors) make up approximately 40% of the drugs in clinical use (1). The natural ligands for the 7TMRs for which drugs have been discovered are themselves primarily small molecules, such as norepinephrine, adenosine, and acetylcholine. Smallmolecule ligands for the subclass of 7TMRs for which the natural ligands are 30-kDa heterodimeric glycoprotein hormones have recently begun to be described, but none have been approved for use in humans. For example, small-molecule agonists (2-5) and an antagonist (6) for the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), and small-molecule agonists (7-9) and antagonists (10-12) for the FSH receptor (FSHR) have been reported. The thyrotropin (thyroid-stimulating hormone, TSH) receptor (TSHR) is the third member of the glycoprotein hormone receptor subfamily. We recently reported smallmolecule agonists (13) and an antagonist (14) for human TSHR; however, the agonists were of low affinity and were shown to activate TSHRs only in a model cell system in which human TSHRs were ectopically over-expressed.The physiologic role of TSHRs in the hypothalamic-pituitarythyroid axis is well known. TSH, which is produced in the thyrotrophs of the anterior pituitary gland, is secreted into the circulation in response to TSH-releasing hormone stimulation and in turn stimulates the function of the thyroid follicular cells (i.e., thyrocytes) leading, in particular, to increases in size ...

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Subclinical Thyroid Dysfunction and Incident Hip Fracture in Older Adults

Lee¹,

Bůžková²,

Fink³

et al. 2010

Arch Intern Med

122

101

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Background Subclinical thyroid dysfunction is common in older adults and affects bone metabolism, but its effects on fracture risk have not been reported. We sought to determine prospectively whether older men and women with subclinical hyperthyroidism or hypothyroidism have an increased risk of hip fracture. Methods Prospective cohort of 3567 US community-dwelling adults, 65 years or older, with biochemically defined subclinical thyroid dysfunction or euthyroidism was enrolled from June 10, 1989, through May 30, 1990, and followed up through 2004. Main outcome measures included incidence and hazard ratios (HRs), with 95% confidence intervals (CIs), of confirmed incident hip fractures for groups with subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroidism as defined at baseline. Results During 39 952 person-years (median follow-up, 13 years), hip fracture incidence (per 1000 men-years) was 13.65 in men with subclinical hyperthyroidism (n = 29) and 10.27 in men with subclinical hypothyroidism (n = 184), both greater than 5.0 in men with euthyroidism (n = 1159). Men with subclinical hypothyroidism had a multivariable-adjusted HR of 2.31 (95% CI, 1.25–4.27); those with subclinical hyperthyroidism, 3.27 (0.99–11.30). After excluding those with baseline use of thyroid-altering medications, men with endogenous subclinical hyperthyroidism had a higher HR of 4.91 (95% CI, 1.13–21.27), as did men with endogenous subclinical hypothyroidism (2.45, 1.27–4.73). Hip fracture incidence (per 1000 women-years) was 8.93 in women with subclinical hypothyroidism (n = 359) and 10.90 in women with subclinical hyperthyroidism (n = 142) compared with 10.18 in women with euthyroidism (n = 1694). No clear association between subclinical dysfunction and fracture was observed in women. Conclusions Older men with subclinical hyperthyroidism or hypothyroidism are at increased risk for hip fracture. Whether treatment of the subclinical syndrome reduces this risk is unknown.

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A Lack of Thyroid Hormones Rather than Excess Thyrotropin Causes Abnormal Skeletal Development in Hypothyroidism

Cited by 108 publications

References 46 publications

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Subclinical Thyroid Dysfunction and Incident Hip Fracture in Older Adults

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