Endocrine Abstracts

Familial Juvenile Hyperuricaemic Nephropathy (FJHN) is an autosomal dominant disorder that is associated with gout and progressive renal failure. FJHN in 43 families has been reported to be caused by mutations in the UMOD gene, which encodes Uromodulin, also known as the Tamm-Horsfall Glycoprotein, and two families have been reported to have mutations in the transcription factor Hepatocyte Nuclear Factor 1β (HNF-1β), mutations of which usually cause maturity-o...

BackgroundOne in 80 pregnancies is ectopic. Chlamydia trachomatis infection is the major risk factor for ectopic pregnancy yet knowledge of the pathogenic events that lead from Chlamydial infection to ectopic pregnancy is unclear. Furthermore, a blood test that can reliably differentiate an ectopic from an intra-uterine pregnancy is not available. The innate immune system is likely to offer protection against Chlamydia and the natural anti-...

T3-receptor alpha (TRa) is the predominant TR isoform in bone. To investigate its function, we analysed mice harbouring a dominant negative R384C mutation in TRa1 (TRa1m/+). The homozygous TRa1m/m mutation is lethal whereas heterozygotes are euthyroid displaying only transient postnatal hypothyroidism. Critically, dominant negative activity of the mutation is overcome by a 10-fold increase in T3, which is achieved by crossing TRa1m/+ mutants wi...

In developmental studies of mice lacking T3-receptor alpha (TRa0/0) and beta (TRb−/−) we demonstrated delayed endochondral ossification, reduced mineralisation and short stature in TRa0/0 mice, despite euthyroidism. In contrast, TRb−/− mice, which display thyroid hormone resistance with elevated T4 and T3 levels, have advanced ossification, increased mineralisation and accelerated growth. T3-target gene studie...

The insulin tolerance test (ITT) is used to determine the integrity of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-somatotroph (GH) axes in patients suspected of ACTH and GH deficiency. In adults a cortisol response <500nmol/L is considered pathological and a GH peak <9mU/L is consistent with severe GH deficiency. Exercise is an alternative stimulus to GH release which may be used to diagnose GH deficiency during childhood but is rarely used during adult li...

T3, GH and IGF-1 are essential for skeletal development. GH acts directly on growth plate chondrocytes and also via a local paracrine pathway involving IGF-1, but it is unclear whether T3 stimulates bone formation directly or indirectly. To address this, we determined expression of GH-receptor, IGF-1 and IGF-1 receptor (IGF-1R) by in situ hybridisation and activation of downstream STAT5 and AKT signalling by immunohistochemistry in growth plates from four T3-receptor (TR) muta...

T3, GH and IGF-1 are essential for skeletal development, growth and bone mineralisation. The major growth-promoting actions of GH occur in epiphyseal chondrocytes via direct effects on GH-receptor expressing cells and via a local paracrine pathway involving IGF-1. There is controversy regarding whether T3-actions in bone are direct or occur via regulation of GH secretion and action. We examined this in mice with a mutation (PV) targeted to either T3-receptor (TR) beta or alpha...

Thyroid hormone (T3) is essential for skeletal development and maintenance of bone mineralisation. T3 actions are mediated by two receptors, TRalpha and TRbeta. Mutations in TRbeta cause autosomal dominant resistance to thyroid hormone (RTH) due to dominant negative activity of the mutant receptor. Short stature and abnormal skeletal development are prominent features of RTH, whereas TRalpha mutations have not been described and are postulated to result in no phenotype or to b...

Although thyroid hormone (T3) and the T3-receptor (TR) alpha gene are essential for skeletal development, T3-signalling pathways in bone have not been characterised. We identified fibroblast growth factor receptor-1 (FGFR1) as a novel T3-inducible gene in osteoblasts by subtraction hybridisation. FGFR1 mRNA was induced 2-3 fold in osteosarcoma cells and primary cultured osteoblasts treated with T3 (0.1-1000nM, 0-48h) and FGFR1 protein was stimulated 2-4 fold over the same peri...

Thyroid hormone (T3) receptor beta (TRbeta) mutations cause resistance to thyroid hormones (RTH), characterised by decreased tissue sensitivity to T3. The TRbetaPV mutation (C-insertion at codon 448 leads to a frameshift of the carboxy-terminal 14 amino acids) was derived from a patient with severe RTH and generates a receptor lacking T3-binding and transactivation activities. Heterozygous mutant mice have a mildly impaired pituitary-thyroid axis; severe RTH and limb shortenin...