Endocrine Abstracts

Early detection, surgery and targeted treatments have seen remarkable improvements in cancer survival. Yet for many patients, cancers still relapse in distant organs after seemingly successful treatment of primary disease. The skeleton is one of the most common sites. Multiple myeloma develops directly in bone, whereas solid tumours, including breast and prostate cancers, spread to bone, often early in the clinical course, giving rise to incurable disease. It remains unclear h...

Kyphosis is a common spinal disorder affecting up to 8.3% of the population, and associated with significant morbidity. Familial and twin studies have implicated a genetic involvement. However, the causative genes have not been identified. Studies investigating the underlying molecular mechanisms are hampered by genetic heterogeneity, small families and variable modes of inheritance displayed by different kindreds. To overcome these limitations, we investigated 12 week old pro...

Kyphosis and scoliosis are common spinal disorders that lead to significant morbidity in childhood, adolescence and adulthood. Familial and twin studies have implicated a genetic involvement, although the causative genes remain to be identified. To facilitate these studies, we investigated 12-week-old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments that included dysmorphology, radiography and dual-energy ...

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 Wellcome Trust Sanger Institute Gene Targeting Programme is deleting all mouse genes and has already generated 400 knockout mice in a C57/BL6N background with a further 4000 genes targeted in ES cells. Two hundred and fifty new knockouts will undergo limited phenotyping each year. However, the programme lacks a sensitive and sufficiently detailed screen for individual physiological systems, each of which requires high throughput methodology and unique expertise. Thus, we p...

Investigations of skeletal dysplasias which are often inherited have yielded important insights in the molecular mechanisms of bone development, osteoporosis and osteoarthritis. However, these studies have been hampered by the lack of available patients and affected families. To overcome this limitation, we have investigated mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for hereditary musculoskeletal disorders. Mice were kept in accordance wi...

Abnormalities of calcium homeostasis such as secondary or tertiary hyperparathyroidism, and renal osteodystrophy often occur in patients with kidney failure. However, investigations of the underlying molecular mechanisms have been hampered by the lack of available tissues from patients and the lack of suitable animal models. We therefore sought to overcome this limitation by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea and identified...

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter-8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compo...

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter-8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compo...

Cushing’s syndrome, which is characterised by excessive circulating glucocorticoid (GC) concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumours, respectively. In the course of our phenotype-driven screens of mouse mutants induced by the chemical mutagen N-ethyl-N-nitrosourea (ENU), we observed a mutant mouse with obesity, hyperglycaemia and low bone mineral density, features that ar...