TSHR as a therapeutic target in Graves’ disease

ABSTRACT

Introduction: Graves’ disease (GD) and thyroid-associated ophthalmopathy (TAO) are thought to result from actions of pathogenic antibodies mediated through the thyrotropin receptor (TSHR). This leads to the unregulated consequences of the antibody-mediated receptor activity in the thyroid and connective tissues of the orbit. Recent studies reveal antibodies that appear to be directed against the insulin-like growth factor-I receptor (IGF-IR).

Areas covered: In this brief article, I attempt to review the fundamental characteristics of the TSHR, its role in GD and TAO, and its relationship to IGF-IR. Strong evidence supports the concept that the two receptors form a physical and functional complex and that IGF-IR activity is required for some of the down-stream signaling initiated through TSHR. Recently developed small molecules and monoclonal antibodies that block TSHR and IGF-IR signaling are also reviewed in the narrow context of their potential utility as therapeutics in GD and TAO. The Pubmed database was searched from its inception for relevant publications.

Expert opinion: Those agents that can interrupt the TSHR and IGF-IR pathways possess the potential for offering more specific and better tolerated treatments of both hyperthyroidism and TAO. This would spare patients exposure to toxic drugs, ionizing radiation and potentially hazardous surgeries.

KEYWORDS:

• Autoimmunity
• Graves’ disease
• ophthalmopathy
• tyrosine kinase

Article highlights

• Detailed characterization of TSHR has allowed its more precise therapeutic targeting

• TSHR appears to play a role in the pathogenesis of thyroid-associated ophthalmopathy as well as the hyperthyroidism associated with Graves’ disease

• TSHR forms a physical/functional complex with IGF-IR

• Components of signaling downstream from TSHR depend on a functional IGF-IR

• It is possible that specific targeting of TSHR as well as IGF-IR will represent clinically useful and specific therapies for both hyperthyroidism and the ocular manifestations of GD.

This box summarizes key points contained in the article

Acknowledgements

The expert assistance of Ms. Darla Kroft in preparing this manuscript is gratefully acknowledged.

Declaration of interest

T. Smith reports holding patents related to the detection of anti-body mediated inflammatory auto-immune disorders (US 6936426), the diagnosis and therapy of antibody-mediated inflammatory autoimmune disorders (US 7998681 and US 8153121), and diagnostic methods related to Graves’ disease and other autoimmune disorders (US 8178304).

Additional information

Funding

This work was supported in part by National Institutes of Health grants EY008976 and 5UM1AI110557, Center for Vision core grant EY007002 from the National Eye Institute, an unrestricted grant from Research to Prevent Blindness, and by the Bell Charitable Foundation.