It Takes Two to Tango: IGF-I and TSH Receptors in Thyroid Eye Disease

Leonard Girnita, Terry J. Smith, Joseph A.M.J.L. Janssen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Scopus)
22 Downloads (Pure)

Abstract

Context: Thyroid eye disease (TED) is a complex autoimmune disease process. Orbital fibroblasts represent the central orbital immune target. Involvement of the TSH receptor (TSHR) in TED is not fully understood. IGF-I receptor (IGF-IR) is overexpressed in several cell types in TED, including fibrocytes and orbital fibroblasts. IGF-IR may form a physical and functional complex with TSHR. Objective: Review literature relevant to autoantibody generation in TED and whether these induce orbital fibroblast responses directly through TSHR, IGF-IR, or both. Evidence: IGF-IR has traditionally been considered a typical tyrosine kinase receptor in which tyrosine residues become phosphorylated following IGF-I binding. Evidence has emerged that IGF-IR possesses kinase-independent activities and can be considered a functional receptor tyrosine kinase/G-protein-coupled receptor hybrid, using the G-protein receptor kinase/β-arrestin system. Teprotumumab, a monoclonal IGF-IR antibody, effectively reduces TED disease activity, proptosis, and diplopia. In addition, the drug attenuates in vitro actions of both IGF-I and TSH in fibrocytes and orbital fibroblasts, including induction of proinflammatory cytokines by TSH and TED IgGs. Conclusions: Although teprotumumab has been proven effective and relatively safe in the treatment of TED, many questions remain pertaining to IGF-IR, its relationship with TSHR, and how the drug might be disrupting these receptor protein/protein interactions. Here, we propose 4 possible IGF-IR activation models that could underlie clinical responses to teprotumumab observed in patients with TED. Teprotumumab is associated with several adverse events, including hyperglycemia and hearing abnormalities. Underpinning mechanisms of these are being investigated. Patients undergoing treatment with drug must be monitored for these and managed with best medical practices.

Original languageEnglish
Pages (from-to)S1-S12
JournalJournal of Clinical Endocrinology and Metabolism
Volume107
Early online date15 Feb 2022
DOIs
Publication statusPublished - Sept 2022

Bibliographical note

Funding Information:
Research support was received from the Swedish Research Council #2021-01247, Swedish Cancer Society grants CAN 2017/1103 and 20 0989 PjF, the Swedish Childhood Cancer Foundation, grant PR2020-0123 Crown Princess Margareta's Foundation for the Visually Impaired, Welander Finsen Foundation, King Gustaf V Jubilee Foundation, Stockholm Cancer Society, Stockholm County and Karolinska Institute, National Institutes of Health grant EY008976, and National Eye Institute core grant EY007003. Schematics were created in part with BioRender.com.

Publisher Copyright:
© 2022 The Author(s).

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