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

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.

Fibrocyte Participation in Thyroid-Associated Ophthalmopathy Suggests New Approaches to Therapy

“…The importance of β-arrestins in the interactions between IGF-IR and TSHR has illuminated a number of potentially important aspects of pathogenic signaling initiated by autoantibodies in GD and TAO (reviewed recently by Girnita et al). 58 Subsequent studies conducted in vitro revealed that IGF-IR inhibition can result in attenuation of responses to TSH, IGF-I, and GD-IgG in CD34 + fibrocytes. 59 Teprotumumab, a fully human IGF-IR-specific monoclonal antibody inhibitor, can attenuate both basal and TSH-dependent expression of Bc activating factor, thyroglobulin, TSHR, sodium-iodide symporter, thyroperoxidase, and IL-10 in CD34 + fibrocytes.…”

“…The importance of β-arrestins in the interactions between IGF-IR and TSHR has illuminated a number of potentially important aspects of pathogenic signaling initiated by autoantibodies in GD and TAO (reviewed recently by Girnita et al ). 58…”

Aktuelle Therapieansätze der endokrinen Orbitopathie – sind die zielgerichteten Therapien die Zukunft?

“…Teprotumumab is an antibody directed against the IGF1 receptor and inhibits its function. Inhibition blocks hyaluronic acid production, which is triggered by TSH-R abs via "cross-talk" to IGF1-R [133]. The antibody has in the past been investigated in cancer therapy studies, but has not found broad clinical use outside of oncology.…”

The Mysterious Universe of the TSH Receptor

“…Indeed, enhanced TSH-R expression has been shown to be influenced by the autoimmune and inflammatory process (85) and to parallel with de novo adipogenesis (82). A role for the IGF-1 receptor has also been suggested and a crosstalk between IGF-1 receptor and the TSH-R is currently accepted as an important phenomenon in the pathophysiology of GO (86)(87)(88)(89)(90).…”