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Thyroid Status during Skeletal Development Determines Adult Bone Structure and Mineralization

Molecular Endocrinology Group (J.H.D.B., S.K., G.R.W.), Division of Medicine and Medical Research Council, Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom; Department of Cell and Molecular Biology (K.N., B.V.), Karolinska Institute, S-171 77 Stockholm, Sweden; Biophysics Oral Growth and Development (A.B., P.G.T.H.), Institute of Dentistry, Barts and The London School of Medicine, Queen Mary University of London, London E1 1BB, United Kingdom; and Department of Prosthetic Dentistry (P.G.T.H.), Eastman Dental Institute, University College London, London WC1X 8LD, United Kingdom

Address all correspondence and requests for reprints to: Graham Williams, Molecular Endocrinology Group, MRC Clinical Sciences Center, Clinical Research Building 5th Floor, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. E-mail: graham.williams{at}ic.ac.uk or Björn Vennström, Department of Cell and Molecular Biology, Karolinska Institute, Box 285, S-171 77 Stockholm, Sweden. E-mail: Bjorn.Vennstrom{at}ki.se.

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 TR1^+/mß^+/– mice, which express a mutant T₃ receptor (TR) 1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TR1^+/mß^+/– 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 TR1^+/mß^–/– mutant mice due to 10-fold elevated hormone levels that allow the mutant TR1 to bind T₃. By contrast, deletion of TRß in TR1^+/+ß^{–/ –} 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 TR1^m/+ß^+/– mice, thyrotoxicosis in TR1^+/+ß^–/– mice, and euthyroidism in TR1^+/ß^–/– double mutants. Thus, TR1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone

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