A Stimulatory Thyrotropin Receptor Antibody Enhances Hyaluronic Acid Synthesis in Graves' Orbital Fibroblasts: Inhibition by an IGF-I Receptor Blocking Antibody
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CONTEXT: Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital fat and extraocular muscle tissues and elevated levels of TSH receptor autoantibodies (TRAb). The expansion of orbital tissues involves accumulation of hyaluronic acid (HA) within the orbit. OBJECTIVE: The objective of the study was to determine whether a monoclonal stimulatory TRAb (M22) impacts HA synthesis in GO orbital cells and, if so, whether this might be blocked by an IGF-I receptor (IGF-IR)-blocking antibody (1H7) or inhibitors of various downstream signaling cascades. DESIGN: GO orbital fibroblast cultures (n = 6) were treated with M22, bovine TSH (bTSH), or IGF-I in serum-free medium. Some cultures also received 1H7, LY294002, rapamycin, or protein kinase A inhibitor. MAIN OUTCOME MEASURES: HA production and phosphorylated Akt levels in media or immunoblotting for phosphorylated Akt were measured. RESULTS: M22 or bTSH stimulated HA synthesis (2.1-fold with 100 ng/ml M22 and 1.9-fold with 10 U/liter bTSH; P < 0.05 each). M22-induced HA synthesis was inhibited by LY294002 or rapamycin but not by protein kinase inhibitor. HA synthesis stimulated by M22 or IGF-I was inhibited by 1H7 (mean 36.6 ± 5.6% and mean 45.8 ± 7.6%, respectively; P < 0.05 each). Similarly, M22- or IGF-I-stimulated Akt phosphorylation was inhibited by 1H7 (mean 54 ± 9.6 and 36.1 ± 8.8%, respectively; P = 0.01 each). CONCLUSIONS: The stimulatory TRAb M22 increases HA production in undifferentiated GO orbital fibroblasts via phosphoinositide 3-kinase/phosphorylated AKT/mammalian target of rapamycin activation. Blockade of IGF-IR inhibits both HA synthesis and Akt phosphorylation induced by M22 or IGF-I in these cells, suggesting that TSH receptor and IGF-IR signaling may be closely linked in the GO orbit.
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Experimental evidence suggests that TRAb antibodies are directly involved in GO pathogenesis.
“Experimental evidence suggests that these antibodies are directly involved in GO pathogenesis (516,542,543).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [543]
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“Experimental evidence suggests that these antibodies are directly involved in GO pathogenesis (516,542,543).”
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Self-citation
- Authors
- Kumar, S., Iyer, S., Bauer, H., Coenen, M., & Bahn, R. S.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Bahn, Rebecca S.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-05
- Volume
- 97
- Issue
- 5
- Pages
- 1681-1687
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3339886
- OpenAlex
- W2081396141
- Cited by
- 84
- References
- 26
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 2 · 2021: 11 · 2020: 9 · 2019: 7 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 11 · 2014: 8 · 2013: 4 · 2012: 1
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Clinic
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK077814, R01DK077814, DK77814)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Ophthalmology and Eye Disorders
- Health Sciences › Medicine › Neurology › Myasthenia Gravis and Thymoma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Ocular Disorders and Treatments
- Keywords
- Graves' ophthalmopathy, TSH receptor antibodies, hyaluronan synthesis, orbital fibroblasts, IGF-1 receptor, phosphatidylinositol 3-kinase/Akt signaling, mTOR signaling, TSH receptor signaling, insulin-like growth factor I, LY294002
- MeSH terms
- Cells, Cultured, Fibroblasts, Humans, Hyaluronic Acid, Receptors, Thyrotropin, Signal Transduction, Receptor, IGF Type 1, Antibodies, Blocking, Graves Ophthalmopathy
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