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Cited by 84Ophthalmology and Eye DisordersMyasthenia Gravis and ThymomaOcular Disorders and Treatments

A Small Molecule Antagonist Inhibits Thyrotropin Receptor Antibody-Induced Orbital Fibroblast Functions Involved in the Pathogenesis of Graves Ophthalmopathy

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Turcu, Adina F., Kumar, Seema, Neumann, Susanne, Coenen, Michael, Iyer, Seethalakshmi, Chiriboga, Pamela, Gershengorn, Marvin C., Bahn, Rebecca S.·2013·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2013-1149PMC PMC3644605
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Abstract

CONTEXT: Graves 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. OBJECTIVE: The 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). DESIGN: Primary 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 MEASURES: cAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed. RESULTS: Compound 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. CONCLUSIONS: Because 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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Authors
Turcu, A. F., Kumar, S., Neumann, S., Coenen, M., Iyer, S., Chiriboga, P., Gershengorn, M. C., & Bahn, R. S.
Affiliations
  • Mayo Clinic (US)
  • National Institutes of Health (US)
  • Division of Endocrinology, Diabetes, Metabolism and Nutrition (A.F.T., M.C., S.I., P.C., R.S.B.), Minnesota 55905
Corresponding author
Bahn, Rebecca S.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2013-05-01
Volume
98
Issue
5
Pages
2153-2159
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2013-1149
PMC
PMC3644605
OpenAlex
W1999444785
Cited by
84
References
23
Citations by year
2025: 5 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 8 · 2015: 10 · 2014: 8 · 2013: 5
FWCI
7.73
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
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, orbital fibroblasts, thyroid-stimulating antibodies, hyaluronan synthesis, cAMP signaling, Akt phosphorylation, adipogenesis, TSH receptor signaling
MeSH terms
Cyclic AMP, Antibodies, Monoclonal, Cells, Cultured, Eye, Fibroblasts, Humans, Hyaluronic Acid, Osmolar Concentration, Phosphorylation, Protein Processing, Post-Translational, Pyridines, Receptors, Thyrotropin, Thyrotropin, Signal Transduction, Immunoglobulins, Thyroid-Stimulating, Graves Ophthalmopathy, Proto-Oncogene Proteins c-akt, Adipose Tissue, White, Quinazolinones, Drug Inverse Agonism, Cell Dedifferentiation

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