Contrasting Skeletal Phenotypes in Mice with an Identical Mutation Targeted to Thyroid Hormone Receptor α1 or β
Open accessAbstract
Thyroid hormone (T(3)) regulates bone turnover and mineralization in adults and is essential for skeletal development. Surprisingly, we identified a phenotype of skeletal thyrotoxicosis in T(3) receptor beta(PV) (TRbeta(PV)) mice in which a targeted frameshift mutation in TRbeta results in resistance to thyroid hormone. To characterize mechanisms underlying thyroid hormone action in bone, we analyzed skeletal development in TRalpha1(PV) mice in which the same PV mutation was targeted to TRalpha1. In contrast to TRbeta(PV) mice, TRalpha1(PV) mutants exhibited skeletal hypothyroidism with delayed endochondral and intramembranous ossification, severe postnatal growth retardation, diminished trabecular bone mineralization, reduced cortical bone deposition, and delayed closure of the skull sutures. Skeletal hypothyroidism in TRalpha1(PV) mutants was accompanied by impaired GH receptor and IGF-I receptor expression and signaling in the growth plate, whereas GH receptor and IGF-I receptor expression and signaling were increased in TRbeta(PV) mice. These data indicate that GH receptor and IGF-I receptor are physiological targets for T(3) action in bone in vivo. The divergent phenotypes observed in TRalpha1(PV) and TRbeta(PV) mice arise because the pituitary gland is a TRbeta-responsive tissue, whereas bone is TRalpha responsive. These studies provide a new understanding of the complex relationship between central and peripheral thyroid status.
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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 [83]
The Discussion (page not supplied) reports accelerated growth and advanced ossification in young TRβ PV mice and attributes their skeletal thyrotoxicosis to elevated T3 acting through TRα in bone. The paper mentions high-bone-turnover osteoporosis as a reported feature of human resistance to thyroid hormone, but does not establish increased turnover or osteoporosis in adult TRβ-mutant mice. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe 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 [83]
Together, the reports define a new genetic disorder, RTHα, characterized by profound and consistent developmental abnormalities of the skeleton that recapitulate findings in mice with dominant-negative Thra mutations.
“Together, these reports define a new genetic disorder, RTHα, characterized by profound and consistent developmental abnormalities of the skeleton that recapitulate findings in mice with dominant-negative Thra mutations [80–85].”
From Thyroid diseases and bone health (2018) · cites this paper as [83]
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Circulating levels of IGF-1 directly regulate bone growth and density
Yakar, S., Rosen, C. J., Beamer, W. G., Ackert-Bicknell, C. L., Wu, Y., Liu, J.-L., Ooi, G. T., Setser, J., Frystyk, J., Boisclair, Y. R., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215463 · Cited by 739 · see citing works
Long-Term Growth in Juvenile Acquired Hypothyroidism:
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Thyroid Hormone Activates Fibroblast Growth Factor Receptor-1 in Bone
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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
A Mutation in the Thyroid Hormone Receptor Alpha Gene
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Thyroid diseases and bone health
Williams, G. R., & Bassett, J. H. D. (2018) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0753-4 · Cited by 276 · see citing works
Self-citationBianco, A. C., Anderson, G., Forrest, D., Galton, V. A., Gereben, B., Kim, B. W., Kopp, P. A., Liao, X. H., Obregon, M. J., Peeters, R. P., et al. (2014) · Thyroid · doi:10.1089/thy.2013.0109 · Cited by 205 · see citing works
The skeletal consequences of thyrotoxicosis
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Self-citationO’Shea, P. J., Guigon, C. J., Williams, G. R., & Cheng, S.-Y. (2007) · Endocrinology · doi:10.1210/en.2007-0114 · Cited by 22 · see citing works
Self-citationRole of Thyroid Hormone Receptor-α1 in Endochondral Ossification
Williams, G. R. (2014) · Endocrinology · doi:10.1210/en.2014-1527 · Cited by 8 · see citing works
Self-citation
- Authors
- O’Shea, P. J., Bassett, J. H. D., Sriskantharajah, S., Ying, H., Cheng, S.-Y., & Williams, G. R.
- Affiliations
- Molecular Endocrinology Group (P.J.O., J.H.D.B, S.S., G.R.W.), Division of Medicine and Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London, W12 0NN, United Kingdom
- Imperial College London (GB)
- National Institutes of Health (US)
- Corresponding author
- Williams, Graham R.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2005-12-01
- Volume
- 19
- Issue
- 12
- Pages
- 3045-3059
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2098416198
- Cited by
- 126
- References
- 3
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 5 · 2021: 1 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 10 · 2013: 8 · 2012: 13
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council (G9803002)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- thyroid hormone receptor alpha 1, thyroid hormone receptor beta, thyroid hormone resistance, skeletal development, thyrotoxicosis, growth plate, GH receptor, IGF-1 receptor, endochondral ossification, intramembranous ossification, bone mineralization, pituitary gland
- MeSH terms
- Animals, Bone and Bones, Bone Development, Hyperthyroidism, Hypothyroidism, Mice, Mutant Strains, Osteogenesis, Phenotype, Pituitary Gland, Receptors, Somatotropin, Triiodothyronine, Bone Density, Frameshift Mutation, Receptor, IGF Type 1, Thyroid Hormone Receptors alpha, Thyroid Hormone Receptors beta, Mice
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