Endocrine Abstracts

The majority of T3 actions are mediated by nuclear thyroid hormone receptors (TRα and TRβ), which act as hormone-inducible transcription factors. TRs are constitutively localised to the nucleus and, in the absence of hormone, bind to T3-response elements (TREs) located in the promoter regions of T3 target genes to mediate transcriptional repression. Entry of T3 to the nucleus and high affinity binding to TRs results in de-r...

Hypothyroidism delays bone formation, whilst thyrotoxicosis accelerates skeletal development but is a risk factor for osteoporosis. We characterized mice with mutation or deletion of T3 receptors, TRα and TRβ, in several genetic backgrounds. Delayed ossification and growth retardation were observed in TRα mutants, whereas TRβ mutants had advanced bone age. Adult TRα mutants had high bone mass, whereas TRβ mutants were osteoporotic. Targ...

Hypothyroidism delays bone development, whilst thyrotoxicosis causes osteoporosis. Recent studies have challenged understanding of skeletal responses to thyroid hormone by proposing TSH as a negative regulator of bone turnover and suggesting bone loss in hyperthyroidism results from TSH deficiency and not T3-excess. To investigate, we characterised mice with mutations or deletions of the genes encoding T3 receptor (TR) α and TRβ. Endochondral ossification was retarde...

Thyrotoxicosis results in osteoporosis and thyroid hormone (T3) stimulates osteoclastic bone resorption by unknown mechanisms. We previously demonstrated that knockout mice lacking thyroid hormone receptor α (TRα0/0) are euthyroid but have high bone mass, whereas mice lacking TRβ (TRβ−/−) are thyrotoxic and have osteoporosis. Tartrate resistant acid phosphatase (TRAcP) staining revealed osteoclast numbers were re...

Thyroid hormones regulate adult bone turnover. Thyrotoxicosis results in high turnover osteoporosis whilst hypothyroidism leads to low bone turnover with increased bone mass and mineralisation. T3-target tissues express thyroid hormone receptor alpha (TRα), thyroid hormone receptor beta (TRβ)or both receptors. TRα1 mediates the actions of T3 in bone and in skeletal cells TRα1 mRNA expression is 12-fold higher than TRβ1. Accordingl...

Thyrotoxicosis is characterised by increased osteoclast activity. Thyroid hormone receptor alpha (TRα) is the predominant TR-isoform in bone and mice lacking TRα have skeletal hypothyroidism with impaired osteoclastic bone resorption. By contrast, mice lacking TRβ have skeletal hyperthyroidism and increased bone resorption. Thus, we hypothesized that T3 acts via TRα to stimulate osteoclastogenesis. Osteoclasts were differentiated in vitro ...

OPUS is a population-based prospective cohort study of post-menopausal women from five European cities. We investigated whether TSH, fT4 and fT3 are associated with fracture risk, bone mineral density (BMD) at hip and spine, bone formation (osteocalcin, procollagen type 1 N-terminal propeptide), bone resorption (N- and C-telopeptides of type 1 collagen, NTX, CTX), pulse rate, grip strength and balance. Vertebral fractures were determined at baseline and 6 years follow-up. Usin...

Thyroid hormone (T3) is an important regulator of skeletal development and bone turnover. Thyrotoxicosis is associated with accelerated growth, advanced bone age and osteoporosis. T3-action in bone is mediated mainly by T3-receptors (TRs). TRβPV mice harbour a dominant-negative mutation in the TRβ gene that impairs negative feedback control of the hypothalamic-pituitary-thyroid axis resulting in elevated thyroid hormone and TSH concentrations. TRβ<sup...

A new genetic disorder has recently been identified that results from mutation of THRA, encoding thyroid hormone receptor α1 (TRα1). Affected children have a high serum T3:T4 ratio, constipation and a variable intellectual deficit, but exhibit a consistently severe skeletal dysplasia. Similar to these patients, Thra1PV/+ mice harbour a mutation that disrupts the C-terminal α-helix of TRα1 and express a domi...

The prohormone T4 represents the majority of circulating thyroid hormones, whereas 80% of the active hormone T3 is derived from T4 by the actions of the type 1 and type 2 deiodinase enzymes (D1 and D2). Local generation of T3 by D2 regulates ligand supply to the nuclear T3-receptor in pituitary, brown adipose tissue and brain, and this enzyme is also expressed in bone. Hypothyroidism in children causes delayed bone age and growth retardation, whereas thyrotoxicosis in adults c...