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A Lack of Thyroid Hormones Rather than Excess Thyrotropin Causes Abnormal Skeletal Development in Hypothyroidism

Molecular Endocrinology Group (J.H.D.B., A.J.W., E.M., R.S., M.A., G.R.W.), Division of Medicine and Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom; Biophysics Centre for 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 Restorative Dental Sciences (P.G.T.H.), University College London Eastman Dental Institute, London WC1X 8LD, United Kingdom; Institut de Génomique Fonctionnelle (F.F., J.S.), Université de Lyon, Université Claude Bernard Lyon I and Ecole Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Institut National de la Recherche Agronomique, 69364 Lyon, France; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire and Service de Génétique Médicale (S.C., G.V.), Université Libre de Bruxelles, B-1070 Bruxelles, Belgium; and Department of Medicine and Committee on Molecular Medicine (R.E.W.) and Departments of Medicine and Pediatrics (S.R.), Committees on Genetics and Molecular Medicine and J. P. Kennedy Mental Retardation and Developmental Disabilities Center, University of Chicago, MC3090, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Graham R. Williams, Molecular Endocrinology Group, 5th Floor Clinical Research Building, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail: graham.williams{at}imperial.ac.uk.

By proposing TSH as a key negative regulator of bone turnover, recent studies in TSH receptor (TSHR) null mice challenged the established view that skeletal responses to disruption of the hypothalamic-pituitary-thyroid axis result from altered thyroid hormone (T₃) action in bone. Importantly, this hypothesis does not explain the increased risk of osteoporosis in Graves’ disease patients, in which circulating TSHR-stimulating antibodies are pathognomonic. To determine the relative importance of T₃ and TSH in bone, we compared the skeletal phenotypes of two mouse models of congenital hypothyroidism in which the normal reciprocal relationship between thyroid hormones and TSH was intact or disrupted. Pax8 null (Pax8^–/–) mice have a 1900-fold increase in TSH and a normal TSHR, whereas hyt/hyt mice have a 2300-fold elevation of TSH but a nonfunctional TSHR. We reasoned these mice must display opposing skeletal phenotypes if TSH has a major role in bone, whereas they would be similar if thyroid hormone actions predominate. Pax8^–/– and hyt/hyt mice both displayed delayed ossification, reduced cortical bone, a trabecular bone remodeling defect, and reduced bone mineralization, thus indicating that the skeletal abnormalities of congenital hypothyroidism are independent of TSH. Treatment of primary osteoblasts and osteoclasts with TSH or a TSHR-stimulating antibody failed to induce a cAMP response. Furthermore, TSH did not affect the differentiation or function of osteoblasts or osteoclasts in vitro. These data indicate the hypothalamic-pituitary-thyroid axis regulates skeletal development via the actions of T₃.

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Ligands:   Thyroid hormone

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