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Thyroid Hormone Excess Rather Than Thyrotropin Deficiency Induces Osteoporosis in Hyperthyroidism

Molecular Endocrinology Group (J.H.D.B., P.J.O., S.S., G.R.W.), Division of Medicine and Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom; Institut Nationale de la Santé et de la Recherche Médicale (INSERM) Unité (U) 577 (B.R., O.C.,), Bordeaux F-33000, France; Université Victor Segalen (B.R., O.C.), Bordeaux F-33076, France; Biophysics Oral Growth and Development (A.B., P.G.T.H.), Institute of Dentistry, Bart’s and The London School of Medicine, Queen Mary University of London, London E1 1BB, United Kingdom; Division of Prosthetic Dentistry (P.G.T.H.), Eastman Dental Institute, University College London, London WC1X 8LD, United Kingdom; Thyroid Study Unit (R.E.W.), Department of Medicine, University of Chicago, Chicago, Illinois 60645; INSERM, U831 (J.-P. R.), Lyon, France; Institut Fédératif de Recherche (IFR) 62, Lyon, France; Université Claude Bernard-Lyon I, Faculté de Médecine Laënnec, Lyon, France; INSERM, U890 (L.M.), Saint-Etienne, France; IFR 62, Lyon, France; Université Jean Monnet, Faculté de Médecine, 42023 Saint-Etienne Cedex 2, France; ProSkelia a Galapagos Company (P.C.-L.), 93230 Romainville, France; Laboratoire de Biologie Moléculaire et Cellulaire de l’Ecole Normale Supérieure de Lyon (J.S.), Unité Mixte de Recherche 5665 Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique 913, Lyon, France

Address all correspondence and requests for reprints to: Graham Williams, Molecular Endocrinology Group, Medical Research Council Clinical Sciences Centre, Clinical Research Building Fifth Floor, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail: graham.williams{at}imperial.ac.uk; or Olivier Chassande, Institut National de la Santé et de la Recherche Médicale Unité 577, Université Victor Segalen Bordeaux 2, Bâtiment 4A, zone Nord, 146, rue Lèo Saignat, 33076 Bordeaux cedex, France. E-mail: Olivier.Chassande{at}bordeaux.inserm.fr.

Thyrotoxicosis is an important but under recognized cause of osteoporosis. Recently, 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 or ß (TR^0/0, TRß^–/–). Remarkably, in the presence of normal circulating thyroid hormone and TSH concentrations, adult TR^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 TRß^–/– 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^0/0 mice, but skeletal thyrotoxicosis in TRß^–/– mice. These studies demonstrate that bone loss in thyrotoxicosis is independent of circulating TSH levels and mediated predominantly by TR, thus identifying TR 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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