Thyroid Status during Skeletal Development Determines Adult Bone Structure and Mineralization
Open accessAbstract
Childhood hypothyroidism delays ossification and bone mineralization, whereas adult thyrotoxicosis causes osteoporosis. To determine how effects of thyroid hormone (T3) during development manifest in adult bone, we characterized TRalpha1(+/m)beta(+/-) mice, which express a mutant T3 receptor (TR) alpha1 with dominant-negative properties due to reduced ligand-binding affinity. Remarkably, adult TRalpha1(+/m)beta(+/-) mice had osteosclerosis with increased bone mineralization even though juveniles had delayed ossification. This phenotype was partially normalized by transient T3 treatment of juveniles and fully reversed in compound TRalpha1(+/m)beta(-/-) mutant mice due to 10-fold elevated hormone levels that allow the mutant TRalpha1 to bind T3. By contrast, deletion of TRbeta in TRalpha1(+/+)beta(-/ -) mice, which causes a 3-fold increase of hormone levels, led to osteoporosis in adults but advanced ossification in juveniles. T3-target gene analysis revealed skeletal hypothyroidism in TRalpha1(m/+)beta(+/-) mice, thyrotoxicosis in TRalpha1(+/+)beta(-/-) mice, and euthyroidism in TRalpha1(+/)beta(-/-) double mutants. Thus, TRalpha1 regulates both skeletal development and adult bone maintenance, with euthyroid status during development being essential to establish normal adult bone structure and mineralization.
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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 [81]
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Role of Thyroid Hormones in Skeletal Development and Bone Maintenance
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- Authors
- Bassett, J. H. D., Nordström, K., Boyde, A., Howell, P. G. T., Kelly, S., Vennström, B., & Williams, G. R.
- Affiliations
- Hammersmith Hospital (GB)
- Department of Cell and Molecular Biology (K.N., B.V.), Karolinska Institute, S-171 77 Stockholm, Sweden;
- Queen Mary University of London (GB)
- Corresponding author
- Williams, Graham R.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-08-01
- Volume
- 21
- Issue
- 8
- Pages
- 1893-1904
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W1998141080
- Cited by
- 125
- References
- 4
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 7 · 2019: 8 · 2018: 4 · 2017: 9 · 2016: 9 · 2015: 2 · 2014: 6 · 2013: 7 · 2012: 15
- FWCI
- 8.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Horserace Betting Levy Board
- Cancerfonden
- Karolinska Institutet
- 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 › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- thyroid hormones, dominant negative receptor, skeletal development, ossification, bone mineralization, osteosclerosis, osteoporosis, hypothyroidism, thyrotoxicosis, thyroid hormone replacement, bone preservation
- MeSH terms
- Animals, Bone and Bones, Bone Development, Calcification, Physiologic, Thyroid Gland, Mice, Knockout, Thyroid Hormone Receptors alpha, Thyroid Hormone Receptors beta, Mice
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