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This version published online on May 8, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0157
Molecular Endocrinology Vol. 0, No. 2007 200701571-
doi:10.1210/me.2007-0157
Copyright © 2007 by the Endocrine Society.
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Submitted on March 27, 2007
Accepted on May 3, 2007

Thyroid status during skeletal development determines adult bone structure and mineralization

J. H. Duncan Bassett, Kristina Nordström, Alan Boyde, Peter G.T. Howell, Shane Kelly, Björn Vennström, and Graham R. Williams*

Molecular Endocrinology Group, Division of Medicine & Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; Department of Cell and Molecular Biology, Karolinska Institute, S-171 77, Stockholm, Sweden; Biophysics Oral Growth and Development, Institute of Dentistry, Bart's and The London School of Medicine, Queen Mary University of London, London, E1 1BB, UK; Department of Prosthetic Dentistry, Eastman Dental Institute, University College London, London, WC1X 8LD, UK

* To whom correspondence should be addressed. E-mail: graham.williams{at}ic.ac.uk.

Childhood hypothyroidism delays ossification and bone mineralization whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T3) during development manifest in adult bone, we characterized TR{alpha}1+/m{beta}+/- mice, which express a mutant T3-receptor (TR) {alpha}1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TR{alpha}1+/m{beta}+/- mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T3-treatment of juveniles and fully reversed in compound TR{alpha}1+/m{beta}-/- mutant mice due to 10-fold elevated hormone levels that allow the mutant TR{alpha}1 to bind T3. By contrast, deletion of TR{beta} in TR{alpha}1+/+{beta}-/- mice, which causes a 3-fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T3-target gene analysis revealed skeletal hypothyroidism in TR{alpha}1m/+{beta}+/- mice, thyrotoxicosis in TR{alpha}1+/+{beta}-/- mice and euthyroidism in TR{alpha}1+/m{beta}-/- double mutants. Thus, TR{alpha}1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization.
Key words: Thyroid hormone receptor {alpha}1 • skeletal development • bone mineralization • osteoporosis • T3

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ
Ligands:   Thyroid hormone



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