ArticleThe Journal of clinical endocrinology and metabolism2013
A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy.
Article in The Journal of clinical endocrinology and metabolism, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 86 citations in OpenAlex.
- Usefulness of TSH receptor antibodies as biomarkers for Graves' ophthalmopathy: a systematic review.Journal of endocrinological investigation · 2018Pooled it
- Redefining Treatment Paradigms in Thyroid Eye Disease: Current and Future Therapeutic Strategies.Journal of clinical medicine · 2025Review
- Thyroid hormone signaling in ocular development and diseases.Biological research · 2025Review
- Effects of linsitinib on M22 and IGF:1-treated 3D spheroids of human orbital fibroblasts.Scientific reports · 2025Article
- Review
- Review
- Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.International journal of molecular sciences · 2023Review
- Unexpected Crosslinking Effects of a Human Thyroid Stimulating Monoclonal Autoantibody, M22, with IGF1 on Adipogenesis in 3T3L-1 Cells.International journal of molecular sciences · 2023Article
- Receptor modulators associated with the hypothalamus -pituitary-thyroid axis.Frontiers in pharmacology · 2023Review
- A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy.Frontiers in immunology · 2023Review
- The risk factors for Graves' ophthalmopathy.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2022Review
- The Study of Biological Activity of a New Thieno[2,3-D]-Pyrimidine-Based Neutral Antagonist of Thyrotropin Receptor.Bulletin of experimental biology and medicine · 2022Article
- Article
- Critical role of mass spectrometry proteomics in tear biomarker discovery for multifactorial ocular diseases (Review).International journal of molecular medicine · 2021Review
- Cytokines as Targets of Novel Therapies for Graves' Ophthalmopathy.Frontiers in endocrinology · 2021Review
- Precision Medicine in Graves' Disease and Ophthalmopathy.Frontiers in pharmacology · 2021Review
- Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease.European thyroid journal · 2020Article
- What Makes Antibodies Against G Protein-Coupled Receptors so Special? A Novel Concept to Understand Chronic Diseases.Frontiers in immunology · 2020Review
- β-Arrestin 1 in Thyrotropin Receptor Signaling in Bone: Studies in Osteoblast-Like Cells.Frontiers in endocrinology · 2020Review
- TSHR Signaling Stimulates Proliferation Through PI3K/Akt and Induction of miR-146a and miR-155 in Thyroid Eye Disease Orbital Fibroblasts.Investigative ophthalmology & visual science · 2019Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
contextGraves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction.
objectiveThe purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH).
designPrimary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling.
main outcome measurescAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed.
resultsCompound 1 inhibited basal cAMP, pAkt, and HA production and that stimulated by M22 in undifferentiated orbital fibroblasts. Inhibition of HA production was dose-dependent, with a half-maximal inhibitory dose of 830 nM. This compound also inhibited MS-1- and bTSH-stimulated cAMP, pAkt, and HA production. Compound 2 did not inhibit basal HA production but did inhibit M22-stimulated HA production.
conclusionsBecause cAMP, pAkt, and HA production are fibroblast functions that are activated via TSHR signaling and are important in the pathogenesis of GO, small molecule TSHR antagonists may prove to be effective in the treatment or prevention of the disease in the future.
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Registered trials
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