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A Thyrotoxic Skeletal Phenotype of Advanced Bone Formation in Mice with Resistance to Thyroid Hormone

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

Address all correspondence and requests for reprints to: Graham R. 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}ic.ac.uk.

Thyroid hormone (T₃) regulates bone turnover and mineralization in adults and is essential for skeletal development during childhood. Hyperthyroidism is an established risk factor for osteoporosis. Nevertheless, T₃ actions in bone remain poorly understood. Patients with resistance to thyroid hormone, due to mutations of the T₃-receptor ß (TRß) gene, display variable phenotypic abnormalities, particularly in the skeleton. To investigate the actions of T₃ during bone development, we characterized the skeleton in TRßPV mutant mice. TRßPV mice harbor a targeted resistance to thyroid hormone mutation in TRß and recapitulate the human condition. A severe phenotype, which includes shortened body length, was evident in homozygous TRß^PV/PV animals. Accelerated growth in utero was associated with advanced endochondral and intramembranous ossification. Advanced bone formation resulted in postnatal growth retardation, premature quiescence of the growth plates, and shortened bone length, together with increased bone mineralization and craniosynostosis. In situ hybridization demonstrated increased expression of fibroblast growth factor receptor-1, a T₃-regulated gene in bone, in TRß^PV/PV perichondrium, growth plate chondrocytes, and osteoblasts. Thus, the skeleton in TRß^PV/PV mice is thyrotoxic and displays phenotypic features typical of juvenile hyperthyroidism.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ

Ligands:   Thyroid hormone

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