A Thyrotoxic Skeletal Phenotype of Advanced Bone Formation in Mice with Resistance to Thyroid Hormone
Open accessAbstract
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.
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The skeletal phenotype in mouse models of RTHβ is due to increased T3 action in cartilage and bone.
“Nevertheless, analysis of the skeletal consequences of mutations of Thrb in mouse models of RTHβ is consistent with a skeletal phenotype of accelerated bone development in juveniles and increased bone turnover with osteoporosis in adults that is due to increased T3 action in cartilage and bone [1, 83, 89–91].”
From Thyroid diseases and bone health (2018) · cites this paper as [91]
Analysis of the skeletal consequences of mutations of Thrb in mouse models of RTHβ is consistent with a skeletal phenotype of accelerated bone development in juveniles and increased bone turnover with osteoporosis in adults.
“Nevertheless, analysis of the skeletal consequences of mutations of Thrb in mouse models of RTHβ is consistent with a skeletal phenotype of accelerated bone development in juveniles and increased bone turnover with osteoporosis in adults that is due to increased T3 action in cartilage and bone [1, 83, 89–91].”
From Thyroid diseases and bone health (2018) · cites this paper as [91]
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Cites
Long-Term Growth in Juvenile Acquired Hypothyroidism:
Rivkees, S. A., Bode, H. H., & Crawford, J. D. (1988) · New England Journal of Medicine · doi:10.1056/nejm198803103181003 · Cited by 272 · see citing works
Thyroid Hormone Activates Fibroblast Growth Factor Receptor-1 in Bone
Stevens, D. A., Harvey, C. B., Scott, A. J., O’Shea, P. J., Barnard, J. C., Williams, A. J., Brady, G., Samarut, J., Chassande, O., & Williams, G. R. (2003) · Molecular Endocrinology · doi:10.1210/me.2003-0137 · Cited by 105 · see citing works
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Molecular Aspects of Thyroid Hormone Actions
Cheng, S.-Y., Leonard, J. L., & Davis, P. J. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0007 · Cited by 1,384 · see citing works
Self-citationRole of Thyroid Hormones in Skeletal Development and Bone Maintenance
Bassett, J. H. D., & Williams, G. R. (2016) · Endocrine Reviews · doi:10.1210/er.2015-1106 · Cited by 540 · see citing works
Self-citationThyroid hormone receptors and resistance to thyroid hormone disorders
Ortiga-Carvalho, T. M., Sidhaye, A. R., & Wondisford, F. E. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2014.143 · Cited by 383 · see citing works
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Self-citationThyroid Hormones Regulate Fibroblast Growth Factor Receptor Signaling during Chondrogenesis
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- Authors
- O’Shea, P. J., Harvey, C. B., Suzuki, H., Kaneshige, M., Kaneshige, K., Cheng, S.-Y., & Williams, G. R.
- Affiliations
- 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
- Hammersmith Hospital (GB)
- National Institutes of Health (US)
- Corresponding author
- Williams, Graham R.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2003-07-01
- Volume
- 17
- Issue
- 7
- Pages
- 1410-1424
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2153204201
- Cited by
- 131
- References
- 2
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2020: 4 · 2019: 5 · 2018: 9 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 8 · 2013: 4 · 2012: 12
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Molecular Endocrinology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- thyroid hormone resistance, thyroid hormone receptor beta, endochondral ossification, intramembranous ossification, craniosynostosis, FGFR1, bone mineralization, skeletal development
- MeSH terms
- Animals, Animals, Newborn, Body Height, Bone and Bones, Bone Development, Craniosynostoses, Female, Growth Plate, Hyperthyroidism, Male, Mice, Mutant Strains, Receptors, Thyroid Hormone, Thyroxine, Bone Density, Receptors, Fibroblast Growth Factor, Limb Deformities, Congenital, Thyroid Hormone Resistance Syndrome, Gene Expression Regulation, Developmental, Receptor Protein-Tyrosine Kinases, Thyroid Hormone Receptors beta, Mice, Receptor, Fibroblast Growth Factor, Type 1
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