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 β (TRβ) gene, display variable phenotypic abnormalities, particularly in the skeleton. To investigate the actions of T3 during bone development, we characterized the skeleton in TRβPV mutant mice. TRβPV mice harbor a targeted resistance to thyroid hormone mutation in TRβ and recapitulate the human condition. A severe phenotype, which includes shortened body length, was evident in homozygous TRβPV/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 TRβPV/Pv perichondrium, growth plate chondrocytes, and osteoblasts. Thus, the skeleton in TRβPV/PV mice is thyrotoxic and displays phenotypic features typical of juvenile hyperthyroidism.