Modulating TSH Receptor Signaling for Therapeutic Benefit

Abstract

Autoimmune thyroid-stimulating antibodies are activating the thyrotropin receptor (TSHR) in both the thyroid and the eye, but different molecular mechanisms are induced in both organs, leading to Graves’ disease (GD) and Graves’ orbitopathy (GO), respectively. Therapy with anti-thyroid drugs to reduce hyperthyroidism (GD) by suppressing the biosynthesis of thyroid hormones has only an indirect effect on GO, since it does not causally address pathogenic TSHR activation itself. GO is thus very difficult to treat. The activated TSHR but also the cross-interacting insulin-like growth factor 1 receptor (IGF-1R) contribute to this issue. The TSHR is a heptahelical G-protein-coupled receptor, whereas the IGF-1R is a receptor tyrosine kinase. Despite these fundamental structural differences, both receptors are phosphorylated by G-protein receptor kinases, which enables β-arrestin binding. Arrestins mediate receptor internalization and also activate the mitogen-activated protein kinase pathway. Moreover, emerging results suggest that arrestin plays a critical role in the cross-interaction of the TSHR and the IGF-1R either in their common signaling pathway and/or during an indirect or potential TSHR/IGF-1R interaction. In this review, novel pharmacological strategies with allosteric small-molecule modulators to treat GO and GD on the level of the TSHR and/or the TSHR/IGF-1R cross-interaction will be discussed. Moreover, monoclonal antibody approaches targeting the TSHR or the IGF-1R and thereby preventing activation of either receptor will be presented. Another chapter addresses the immunomodulation to treat GO using TSHR-derived peptides targeting the human leukocyte antigen DR isotope (HLA-DR), which is a feasible approach to tackle GO, since HLA-DR and TSHR are overexpressed in orbital tissues of GO patients.

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

“…The fact that they may not be widely available or affordable, as well as the lack of information, say, on the need of subsequent rehabilitative surgery, further add to their current limitations. As multiple pathogenic pathways are implicated in GO, several targeted therapies are worth exploring in clinical trials, e.g., monoclonal antibodies and/or small molecules targeting the TSHR (187,188) or the CD40 molecule expressed in both thyrocytes and orbital fibroblasts (189), or anti-IL-23/anti-IL-17 for the IL-23/IL-17 axis and sirolimus for the mTOR pathway (190). Worthwhile is also a modulating impact on the microbiome in patients with GO (191).…”

MiR-143 Targets IGF-1R to Suppress Autoimmunity in Thyroid-Associated Ophthalmopathy

“… 4 , 36 The exact mechanism in the progression of TAO is unclear although several studies implicate TSHR and IGF-1R, which are both upregulated in the OFs of patients with TAO. 5 , 37 The miRNA regulation of genes involved in TAO is gaining interest, 38 therefore, in our study, we focused on miRNA that may be involved in the regulation of the inflammasome in TAO using relevant markers such as NLRP3. We found a number of miRNAs that were differentially regulated in the orbital connective tissue of TAO patients and confirmed that three of these were significantly upregulated (miR-22, miR-27b, and miR-378) and one was significantly downregulated (miR-143).…”

“…Several studies have arrived at similar conclusions, the two receptors share interacting signal pathways but may not necessarily activate each other. 5 , 9 However, immunoprecipitation results in some studies have suggested that TSHR and IGF-1R may colocalize. 13 …”

“… 4 Although different mechanisms give rise to Grave’s disease and TAO they both involve the activities of thyroid-stimulating hormone receptor (TSHR) and TSHR-stimulating antibodies (TSAb) in the thyroid and the orbit. 5 , 6 The exogenous expression of TSHR is known to induce both Grave’s disease and TAO in animal models. 7 Antibodies against TSHR (TRAb) are found at high levels in patients with Grave’s disease and are believed to correlate with the severity of TAO.…”

Development of Low-Molecular-Weight Allosteric Agonist of Thyroid-Stimulating Hormone Receptor with Thyroidogenic Activity

“…An approach to stimulate the TSH receptor may be the use of allosteric regulators with the activity of full agonists [ 5 , 6 ]. Their characteristic feature is the ability to stimulate receptors of pituitary glycoprotein hormones that contain inactivating mutations in the ectodomain and are, therefore, insensitive to hormones [ 5 ].…”