ArticleThyroid : official journal of the American Thyroid Association2012
A drug-like antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves' orbital fibroblasts.
Article in Thyroid : official journal of the American Thyroid Association, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 60 citations in OpenAlex.
- TSHR-Targeting Nucleic Acid Aptamer Treats Graves' Ophthalmopathy via Novel Allosteric Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Somatostatin Receptor Type 2 and Thyroid-Stimulating Hormone Receptor Expression in Oncocytic Thyroid Neoplasms: Implications for Prognosis and Treatment.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2023Article
- 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
- Mechanisms in Graves Eye Disease: Apoptosis as the End Point of Insulin-Like Growth Factor 1 Receptor Inhibition.Thyroid : official journal of the American Thyroid Association · 2022Article
- Thyroid-Stimulating Hormone Inhibits Insulin Receptor Substrate-1 Expression and Tyrosyl Phosphorylation in 3T3-L1 Adipocytes by Increasing NF-Disease markers · 2022Article
- Expression of Endogenous Putative TSH Binding Protein in Orbit.Current issues in molecular biology · 2021Article
- Expression and Role of Thyrotropin Receptors in Proopiomelanocortin-Producing Pituitary Cells.Thyroid : official journal of the American Thyroid Association · 2021Article
- Orbital Signaling in Graves' Orbitopathy.Frontiers in endocrinology · 2021Review
- Modulating TSH Receptor Signaling for Therapeutic Benefit.European thyroid journal · 2020Article
- Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease.European thyroid journal · 2020Article
- Is There Evidence for IGF1R-Stimulating Abs in Graves' Orbitopathy Pathogenesis?International journal of molecular sciences · 2020Review
- The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells.Cells · 2020Review
- A Gq Biased Small Molecule Active at the TSH Receptor.Frontiers in endocrinology · 2020Article
- Potential Roles of CD34+ Fibrocytes Masquerading as Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy.The Journal of clinical endocrinology and metabolism · 2019Review
- Editorial: TSH Receptor and Autoimmunity.Frontiers in endocrinology · 2019Article
- TSHR as a therapeutic target in Graves' disease.Expert opinion on therapeutic targets · 2017Review
- Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work.Frontiers in endocrinology · 2017Review
- Rearrangement of the Extracellular Domain/Extracellular Loop 1 Interface Is Critical for Thyrotropin Receptor Activation.The Journal of biological chemistry · 2016Article
- The "TSH Receptor Glo Assay" - A High-Throughput Detection System for Thyroid Stimulation.Frontiers in endocrinology · 2016Article
- Elevated follicular helper T cells and expression of IL-21 in thyroid tissues are involved in the pathogenesis of Graves' disease.Immunologic research · 2015Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundFibroblasts (FIBs) within the retro-orbital space of patients with Graves' disease (GOFs) express thyrotropin receptors (TSHRs) and are thought to be an orbital target of TSHR-stimulating autoantibodies in Graves' ophthalmopathy (GO). Recently, we developed a low molecular weight, drug-like TSHR antagonist (NCGC00229600) that inhibited TSHR activation in a model cell system overexpressing TSHRs and in normal human thyrocytes expressing endogenous TSHRs. Herein, we test the hypothesis that NCGC00229600 will inhibit activation of TSHRs endogenously expressed in GOFs.
methodsThree strains of GOFs, previously obtained from patients with GO, were studied as undifferentiated FIBs and after differentiation into adipocytes (ADIPs), and another seven strains were studied only as FIBs. ADIP differentiation was monitored by morphology and measurement of adiponectin mRNA. FIBs and ADIPs were treated with the TSH- or TSHR-stimulating antibody M22 in the absence or presence of NCGC00229600 and TSHR activation was monitored by cAMP production.
resultsFIBs contained few if any lipid vesicles and undetectable levels of adiponectin mRNA, whereas ADIPs exhibited abundant lipid vesicles and levels of adiponectin mRNA more than 250,000 times greater than FIBs; TSHR mRNA levels were 10-fold higher in ADIPs than FIBs. FIBs exhibited higher absolute levels of basal and forskolin-stimulated cAMP production than ADIPs. Consistent with previous findings, TSH stimulated cAMP production in the majority of ADIP strains and less consistently in FIBs. Most importantly, NCGC00229600 reduced both TSH- and M22-stimulated cAMP production in GOFs.
conclusionsThese data confirm previous findings that TSHR activation may cause increased cAMP production in GOFs and show that NCGC00229600 can inhibit TSHR activation in GOFs. These findings suggest that drug-like TSHR antagonists may have a role in treatment of GO.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.