Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 13 P16

SFEBES2007 Poster Presentations Bone (16 abstracts)

Wnt/β-catenin signalling is abrogated in mice with a targeted mutation in the thyroid hormone receptor (TR) β gene and a thyrotoxic skeletal phenotype

Patrick J O’Shea 1 , Sean Davis 3 , Robert L Walker 3 , Paul S Meltzer 3 , Graham R Williams 2 & Sheue-yann Cheng 1


1Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, MD 20892-4264, United States; 2Molecular Endocrinology Group, Division of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, W12 0NN, United Kingdom; 3Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892-4264, United States.


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. TRβPV mice consequently exhibit advanced endochondral and intramembranous ossification with persistent short stature that results from skeletal thyrotoxicosis. To investigate mechanisms underlying advanced bone formation in TRβPV mice, primary osteoblast RNA was obtained from wild-type and homozygous TRβPV/PV littermate mice and expression profiles of 24,000 genes were determined in cDNA microarray studies. Of a subset of 192 differentially expressed genes, 85 were up-regulated in TRβPV/PV mice whereas 107 were down-regulated. Functional analysis software was used to cluster differentially expressed genes into groups with similar molecular functions. Up-regulation of cyclin D1 and frizzled-7 in TRβPV/PV osteoblasts implicated altered Wnt/β-catenin signalling in the TRβPV phenotype. Gain-of-function mutations of the Wnt-activated LRP5/frizzled co-receptor cause high bone density, whereas loss-of-function mutations cause osteoporosis. Thus, real-time PCR array analysis was employed to characterise expression profiles of the 84 genes involved in mediating Wnt-activated signal transduction pathways. These studies revealed generalised down-regulation of the Wnt pathway in TRβPV/PV osteoblasts, and the findings were validated by independent quantitative RT-PCR studies in primary osteoblasts. In further experiments, murine osteoblastic MC3T3 cells were transfected with a β-catenin responsive T-cell factor reporter gene. T3-treatment resulted in reduced β-catenin expression in Western blots and reduced reporter gene activity, indicating that T3 inhibits β-catenin signal transduction in osteoblasts. These data suggest that reduced Wnt/β-catenin signalling contributes to the advanced bone formation observed in TRβPV mice and may be implicated in osteoporosis associated with thyrotoxicosis.

Volume 13

Society for Endocrinology BES

Society for Endocrinology 

Browse other volumes

Article tools

My recent searches

No recent searches.