Endocrine Abstracts

Thyroid hormone (T3) is required for skeletal development during childhood and T3 regulates bone turnover and mineralisation in adults. Thyrotoxicosis is an established risk factor for osteoporosis. We and others have shown that T3 receptors (TRs) are expressed in osteoblasts and growth plate chondrocytes, which represent primary T3-target cells in the skeleton. T3 effects on osteoclast-mediated bone resorption are thought to be mediated by osteoblasts via paracrine pathways. ...

FGFs and T3 are required for skeletal development. Activating mutations of FGF receptor-1 (FGFR-1) and FGFR-2 cause craniosynostosis, whilst FGFR-3 is a negative regulator of chondrocyte proliferation and activating mutations cause achondroplasia. Childhood hypothyroidism causes delayed ossification and growth retardation, whereas thyrotoxicosis accelerates bone development, induces premature growth plate and skull suture closure and causes short stature and craniosynostosis. ...

T3 and fibroblast growth factors (FGFs) are critical regulators of chondrocyte proliferation during bone formation and we identified recently that T3 modulates skeletal FGF receptor-1 (FGFR1) activity. FGFRs signal via several routes including mitogen-activated protein kinase (MAPK), STAT and phospholipase C gamma pathways. Mechanisms determining which pathways are activated by FGFRs are poorly understood but include alternative splicing of exons encoding variable domains with...

Primary aldosteronism (PA) has a prevalence of 5–15% in the general population with hypertension and patients with PA display an increased frequency of target organ damage and cardiovascular damage than patients with hypertension with matched cardiovascular risk profiles. The unilateral and bilateral forms of PA are treated differently usually surgically (unilateral PA) or by antagonism of the receptor for aldosterone (bilateral PA). Medically-treated patients with PA hav...

Background: Post-translational modification (PTM) of antigens has been shown to play a role in the pathogenesis of autoimmune disorders. In coeliac disease (CD), tissue transglutaminase (tTG) deamidates gliadin peptides to activate the immune response against gut endomysium. CD is six times more prevalent in Type 1 diabetes (T1D) patients than in the general population.Hypothesis: tTG also modifies auto-antigens implicated in the pathogenesis of T1D, lea...

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...

The glycoprotein hormone, TSH, is synthesized and secreted by thyrotrophs in the anterior pituitary gland. It acts at the TSH receptor (TSHR), a 7-transmembrane G-protein coupled cell membrane receptor expressed in thyroid follicular cells. The TSHR, thus, plays a key role in the regulation of thyroid status and growth of the thyroid gland. In recent years TSHR expression has also been identified in a wide variety of extra-thyroidal tissues including: anterior pituitary; hypot...

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...

Osteoporosis is characterised by bone fragility with increased susceptibility to fracture. The burden of osteoporosis already costs the NHS over £1.7 billion per annum but its prevalence is increasing. The skeleton is continually remodelled in response to endocrine, paracrine and mechanical signals by the coupled activities of osteoclasts and osteoblasts. Nevertheless, the continuous process of bone turnover results in an inexorable loss of bone because osteoblast-mediate...

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...