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Contrasting Skeletal Phenotypes in Mice with an Identical Mutation Targeted to Thyroid Hormone Receptor 1 or ß

Molecular Endocrinology Group (P.J.O., J.H.D.B, S.S., G.R.W.), Division of Medicine and Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, W12 0NN, United Kingdom; and Gene Regulation Section (H.Y., S.-y.C.), Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4264

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

Thyroid hormone (T₃) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T₃ receptor ß^PV (TRß^PV) mice in which a targeted frameshift mutation in TRß results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TR1^PV mice in which the same PV mutation was targeted to TR1. In contrast to TRß^PV mice, TR1^PV mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TR1^PV mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRß^PV mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T₃ action in bone in vivo. The divergent phenotypes observed in TR1^PV and TRß^PV mice arise because the pituitary gland is a TRß-responsive tissue, whereas bone is TR responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone

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