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A thyrotoxic skeletal phenotype of advanced bone formation in mice with resistance to thyroid hormone
Patrick J O'Shea1, Clare B Harvey, Hideyo Suzuki
1Molecular Endocrinology Group, Division of Medicine and Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, United Kingdom.
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.
Insights
Thyroid hormone (T3) resistance in mice causes advanced bone formation in utero, leading to shorter bones and growth plate closure. This thyrotoxic skeleton mimics juvenile hyperthyroidism, revealing T3
Area of Science:
- Endocrinology
- Skeletal Biology
- Genetics
Background:
- Thyroid hormone (T3) is crucial for bone turnover, mineralization, and skeletal development.
- Hyperthyroidism is a known risk factor for osteoporosis, but T3's specific bone actions are unclear.
- Mutations in the T3-receptor beta (TRbeta) gene cause resistance to thyroid hormone (RTH), leading to skeletal abnormalities.
Purpose of the Study:
- To investigate the role of T3 in skeletal development using a mouse model of RTH.
- To characterize the skeletal phenotype of TRbetaPV mutant mice, which mimic human RTH.
Main Methods:
- Characterization of the skeletal phenotype in TRbetaPV mutant mice.
- In situ hybridization to assess gene expression in bone tissues.
Main Results:
- TRbetaPV/PV mice exhibited shortened body length, advanced in utero growth, and accelerated ossification.
- Postnatal development showed growth retardation, premature growth plate senescence, shortened bones, increased mineralization, and craniosynostosis.
- Increased expression of fibroblast growth factor receptor-1 was observed in TRbetaPV/PV bone cells.
Conclusions:
- The TRbetaPV/PV mouse skeleton displays thyrotoxic features, mirroring juvenile hyperthyroidism.
- T3 resistance significantly impacts skeletal development, leading to premature bone maturation and growth arrest.