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This version published online on February 27, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0033
A more recent version of this article appeared on May 1, 2007
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Submitted on January 18, 2007
Accepted on February 20, 2007

Thyroid hormone excess rather than TSH deficiency induces osteoporosis in hyperthyroidism

J. H. Duncan Bassett, Patrick J. O'Shea, Srividya Sriskantharajah, Bénédicte Rabier, Alan Boyde, Peter G.T. Howell, Roy E. Weiss, Jean-Paul Roux, Luc Malaval, Phillipe Clement-Lacroix, Jacques Samarut, Olivier Chassande, and Graham R. Williams*

Molecular Endocrinology Group, Division of Medicine & MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK; INSERM U577, Bordeaux, F-33000 France; Université Victor Segalen, Bordeaux, F-33076 France; Biophysics OGD, Institute of Dentistry, Bart's and The London School of Medicine, Queen Mary University of London, London, E1 1BB, UK; Division of Prosthetic Dentistry, Eastman Dental Institute, University College London, London WC1X 8LD; Thyroid Study Unit, Department of Medicine, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60645, USA; INSERM, U831, Lyon, France; IFR 62, Lyon, France; Université Claude Bernard-Lyon I, Faculté de Médecine Laënnec, Lyon, France; INSERM, U890, Saint-Etienne, France; IFR 62, Lyon, France; Université Jean Monnet, Faculté de Médecine, Saint-Etienne, France; ProSkelia a Galapagos Company, Romainville, France; Laboratoire de Biologie Moléculaire et Cellulaire de l'ENS de Lyon, UMR 5665 CNRS, LA 913 INRA, Lyon, France

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

Thyrotoxicosis is an important but under-recognized cause of osteoporosis. Recently, thyroid stimulating hormone (TSH) deficiency, rather than thyroid hormone excess, has been suggested as the underlying cause. To investigate the molecular mechanism of osteoporosis in thyroid disease, we characterized the skeleton in mice lacking either thyroid hormone receptor {alpha} or {beta} (TR{alpha}0/0, TR{beta}-/-). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TR{alpha}0/0 mice had osteosclerosis accompanied by reduced osteoclastic bone resorption, whereas juveniles had delayed endochondral ossification with reduced bone mineral deposition. By contrast, adult TR{beta}-/- mice with elevated TSH and thyroid hormone levels were osteoporotic with evidence of increased bone resorption, whereas juveniles had advanced ossification with increased bone mineral deposition. Analysis of T3 target gene expression revealed skeletal hypothyroidism in TR{alpha}0/0 mice, but skeletal thyrotoxicosis in TR{beta}-/- mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TR{alpha}, thus identifying TR{alpha} as a novel drug target in the prevention and treatment of osteoporosis.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ
Ligands:   Thyroid hormone



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