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Thyroid Hormone Activates Fibroblast Growth Factor Receptor-1 in Bone
Open accessAbstract
Thyroid hormone (T3) and the T3 receptor (TR) alpha gene are essential for bone development whereas adult hyperthyroidism increases the risk of osteoporotic fracture. We isolated fibroblast growth factor receptor-1 (FGFR1) as a T3-target gene in osteoblasts by subtraction hybridization. FGFR1 mRNA was induced 2- to 3-fold in osteoblasts treated with T3 for 6-48 h, and FGFR1 protein was stimulated 2- to 4-fold. Induction of FGFR1 was independent of mRNA half-life and abolished by actinomycin D and cycloheximide, indicating the involvement of an intermediary protein. Fibroblast growth factor 2 (FGF2) stimulated MAPK in osteoblasts, and pretreatment with T3 for 6 h induced a more rapid response to FGF that was increased in magnitude by 2- to 3-fold. Similarly, T3 enhanced FGF2-activated autophosphorylation of FGFR1, but did not modify FGF2-induced phosphorylation of the docking protein FRS2. These effects were abolished by the FGFR-selective inhibitors PD166866 and PD161570. In situ hybridization analyses of TRalpha-knockout mice, which have impaired ossification and skeletal mineralization, revealed reduced FGFR1 mRNA expression in osteoblasts and osteocytes, whereas T3 failed to stimulate FGFR1 mRNA or enhance FGF2-activated MAPK signaling in TRalpha-null osteoblasts. These findings implicate FGFR1 signaling in T3-dependent bone development and the pathogenesis of skeletal disorders resulting from thyroid disease.
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“Although the thyroid hormone T3 modulates FGFR1 signaling [18,19,20], no explicit genotype-phenotype correlation links this variant to thyroid dysfunction.”
From Strengthening the Role of PSMC5 as a Potential Gene Associated with Neurodevelopmental Disorders (2025) · cites this paper as [19]
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Cites
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Endogenous Hormones and the Risk of Hip and Vertebral Fractures among Older Women
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Role of Thyroid Hormones in Skeletal Development and Bone Maintenance
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Self-citationSkeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism
Quarles, L. D. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2011.218 · Cited by 276
The molecular actions of thyroid hormone in bone
Duncan Bassett, J. H., & Williams, G. R. (2003) · Trends in Endocrinology & Metabolism · doi:10.1016/s1043-2760(03)00144-9 · Cited by 261
Self-citationMartin, A., Liu, S., David, V., Li, H., Karydis, A., Feng, J. Q., & Quarles, L. D. (2011) · The FASEB Journal · doi:10.1096/fj.10-177816 · Cited by 254
Bianco, 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
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Metadata
- Authors
- 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.
- Affiliations
- Hammersmith Hospital (GB)
- Imperial College London (GB)
- University of Manchester (GB)
- École Normale Supérieure de Lyon (FR)
- Corresponding author
- Williams, Graham R.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2003-09
- Volume
- 17
- Issue
- 9
- Pages
- 1751-1766
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W1964583412
- Cited by
- 105
- References
- 57
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 1 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 8 · 2013: 7 · 2012: 8
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Wellcome Trust (050570)
- Nuffield Foundation
- Medical Research Council (G9803002)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- thyroid hormones, FGFR1, FGFR1 signaling, FGF2, MAPK signaling, osteoblasts, osteocytes, skeletal development, thyroid dysfunction, osteoporosis, skeletal mineralization, FRS2
- MeSH terms
- Animals, Bone and Bones, Osteoblasts, Phosphorylation, Phosphotransferases, Pyrimidines, Thyroid Gland, Triiodothyronine, Urea, Signal Transduction, Fibroblast Growth Factor 2, Receptors, Fibroblast Growth Factor, Receptor Protein-Tyrosine Kinases, Mitogen-Activated Protein Kinases, Mice, Receptor, Fibroblast Growth Factor, Type 1
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