title: A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone.
abstract: 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 beta (TRbeta) gene, display variable phenotypic abnormalities, particularly in the skeleton. To investigate the actions of T3 during bone development, we characterized the skeleton in TRbetaPV mutant mice. TRbetaPV mice harbor a targeted resistance to thyroid hormone mutation in TRbeta and recapitulate the human condition. A severe phenotype, which includes shortened body length, was evident in homozygous TRbetaPV/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 TRbetaPV/PV perichondrium, growth plate chondrocytes, and osteoblasts. Thus, the skeleton in TRbetaPV/PV mice is thyrotoxic and displays phenotypic features typical of juvenile hyperthyroidism.
authors.affiliation: Molecular Endocrinology Group, Division of Medicine and Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: O'Shea
authors.forename: Clare B
authors.initials: CB
authors.lastname: Harvey
authors.forename: Hideyo
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneshige
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kaneshige
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
authors.forename: Graham R
authors.initials: GR
authors.lastname: Williams
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001827:Body Height / Q000235:genetics; D015519:Bone Density; D001846:Bone Development / Q000235:genetics*; D001842:Bone and Bones / Q000002:abnormalities; D003398:Craniosynostoses / Q000235:genetics / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate; D006980:Hyperthyroidism / Q000235:genetics; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics / Q000503:physiopathology*; D013974:Thyroxine / Q000097:blood
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D013974:Thyroxine