Endocrine Abstracts

The classical genomic actions of triiodothyronine (T3) are mediated by high-affinity nuclear receptors that directly regulate gene expression. By contrast, the non-genomic effects of thyroid hormones occur rapidly and are unaffected by inhibitors of transcription and protein synthesis. The genomic actions of thyroid hormone have an established role in the development, differentiation and homeostatic maintenance of target tissues. The THRA and THRB gene...

Disruption of the HPT-axis during growth profoundly influences skeletal development and effects may not be reversed fully following correction of thyroid status. Adult thyrotoxicosis leads to increased bone turnover and is an established risk factor for osteoporotic fracture. The conventional view that skeletal responses to abnormal thyroid status result solely from altered T3 action in bone has, however, been questioned by studies proposing TSH as a negative regula...

T3 is essential for normal skeletal development. Childhood hypothyroidism causes delayed bone formation, whereas T3-excess accelerates growth and epiphyseal closure. Fibroblast growth factors (FGFs) act via receptor tyrosine kinases (FGFRs) to inhibit chondrocyte proliferation, matrix production and skeletal maturation. Dimerisation of FGFRs and their functional interaction with FGFs requires heparan sulphate proteoglycans (HSPGs). We recently showed that T3 induces FGFR-1 exp...

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...

Local regulation of T3 action in bone and cartilage is a novel mechanism underlying the pathogenesis of osteoarthritis (OA). Accelerated chondrocyte differentiation is a hallmark of OA and T3 regulates this process. The type 1 and 2 deiodinases (D1, D2) convert the pro-hormone T4 to the active hormone T3 whilst D3 inactivates both T3 and T4. D1 contributes to circulating T3 levels and local T3</s...

T3 is essential for skeletal development and its actions are mediated by two nuclear receptors (TRs), with TR alpha (TRa) being functionally predominant in bone. The TRa1 isoform binds T3 with high affinity and activates target gene expression in response to hormone. TRa2, however, does not bind T3 or regulate transcription in response to hormone. Intriguingly, TRa2 is expressed at high levels from early in development in all tissues and is conserved in all mammals, although i...

Following the establishment of a telephone clinic follow-up for patients receiving radioiodine for recurrent thyrotoxicosis, we wished to further improve our results in achieving hypo(eu)thyroidism while minimising the risk of transient hyperthyroidism and thyroid storm post-therapy. Although not widely used, lithium has been shown to increase the effectiveness of radioiodine therapy, leading to prompter control of hyperthyroidism. Since August 2001, patients undergoing radioi...

Articular cartilage maintenance and repair is regulated by numerous endocrine and paracrine factors. Investigation of molecular mechanisms underlying osteoarthritis (OA) is limited by inability to identify early stage disease and individuals at risk of progression. Susceptibility to OA is genetically determined and the availability of mice from the International Knockout Mouse Consortium with deletions of every known gene provides a unique opportunity to investigate its pathop...

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 ...