Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab

University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Best Practice & Research: Clinical Endocrinology & Metabolism (Impact Factor: 4.6). 06/2012; 26(3):291-302. DOI: 10.1016/j.beem.2011.10.002
Source: PubMed


The etiology of Graves' orbitopathy (GO) remains enigmatic and thus controversy surrounds its pathogenesis. The role of the thyroid stimulating hormone receptor (TSHR) and activating antibodies directed against it in the hyperthyroidism of Graves' disease (GD) is firmly established. Less well elucidated is what part the TSHR pathway might play in the development of GO. Also uncertain is the participation of other cell surface receptors in the disease. Elevated levels of insulin-like growth factor-1 receptor (IGF-1R) have been found in orbital fibroblasts as well as B and T cells from patients with GD. These abnormal patterns of IGF-1R display are also found in rheumatoid arthritis and carry functional consequences. In addition, activating IgGs capable of displacing IGF-1 from IGF-1R have also been detected in patients with these diseases. IGF-1R forms a complex with TSHR which is necessary for at least some of the non-canonical signaling observed following TSHR activation. Functional TSHR and IGF-1R have also been found on fibrocytes, CD34⁺ bone marrow-derived cells from the monocyte lineage. Levels of TSHR on fibrocytes greatly exceed those found on orbital fibroblasts. When ligated by TSH or M22, a TSHR-activating monoclonal antibody, fibrocytes produce extremely high levels of several cytokines and chemokines. Moreover, fibrocytes infiltrate both the orbit and thyroid in GD. In sum, based on current evidence, IGF-1R and TSHR can be thought of as "partners in crime". Involvement of the former probably transcends disease boundaries, while TSHR may not.

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    • "cytokines) or by direct cellular interaction (Bahn, 2010). Moreover, orbital fibroblasts in GO may be activated by stimulatory autoantibodies directed against the TSHR and the insulin-like growth factor-1 receptor (IGF-1R) (Bahn, 2010; Smith et al., 2012). The activated orbital fibroblasts increase their proliferative activity, produce inflammatory mediators, differentiate into adipocytes and myofibroblasts and produce excess amounts of extracellular matrix (ECM) components. "
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    ABSTRACT: Graves' ophthalmopathy (GO) is an extra-thyroidal complication of Graves' disease (GD; Graves' hyperthyroidism) characterized by orbital tissue inflammation, expansion, remodeling and fibrosis. Although the initiating trigger of GO is still indistinct, excessive orbital fibroblast activity is at the heart of its pathogenesis. Orbital fibroblasts are activated by cellular interactions with immune cells and the soluble factors they secrete. Orbital fibroblasts, especially from GO patients, express the thyrotropin receptor (TSH-receptor; TSHR), and activation of the orbital fibroblast population by stimulatory autoantibodies directed against the TSHR may provide an important link between GD and GO. Furthermore, stimulatory autoantibodies directed against the insulin-like growth factor-1 receptor have been proposed to contribute to orbital fibroblast activation in GO. Activated orbital fibroblasts produce inflammatory mediators thereby contributing to the orbital inflammatory process in GO. Moreover, orbital fibroblasts exhibit robust proliferative activity and extracellular matrix (especially hyaluronan) synthesizing capacity and can differentiate into adipocytes and myofibroblasts with disease progression, thereby contributing to tissue expansion/remodeling and fibrosis in GO. Orbital fibroblasts, especially those from GO patients, exhibit a hyper-responsive phenotype when compared to fibroblasts from other anatomical regions, which may further contribute to GO pathogenesis. Fibrocytes have been identified as additional source of orbital fibroblasts in GO, where they may contribute to orbital tissue inflammation, adipogenesis and remodeling/fibrosis. This review addresses our current view on the role that orbital fibroblasts fulfill in GO pathogenesis and both established as well as less established not fully crystallized concepts that need future studies will be discussed.
    No preview · Article · Jan 2016 · Experimental Eye Research
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    • "Multiple genes, including both immune regulatory genes and thyroid-specific genes have been reported to contribute to AITD susceptibility (Invernizzi et al., 2009; Smith et al., 2012). TSHR is a thyroid specific gene, located on chromosome 14q31, close to the main locus of susceptibility to Graves' disease (Tomer et al., 1998; Tomer et al., 1997). "

    Full-text · Article · Dec 2015
    • "TSH and TSAbs bind primarily to TSHR via interactions with regions within the extracellular domain [33]. The receptor signaling is induced by ligand binding and transduced by the intracellular surface of the transmembrane helices and the carboxyl-terminal tail of TSHR interacting with G-proteins and arrestins [33, 34]. Antagonists that inhibit TSHR signaling directly by binding to the TSHR are promising new drug treatments. "
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    ABSTRACT: Although there are adequate therapies for Graves' hyperthyroidism, mild to moderate Graves' orbitopathy (GO) is usually treated symptomatically whereas definitive therapy is reserved for severe, vision-threatening GO. Importantly, none of the treatment regimens for Graves' disease used today are directed at the pathogenesis of the disease. Herein, we review some aspects of what is known about the pathogenesis of these 2 major components of Graves' disease, specifically the apparent important roles of the TSH and IGF-1 receptors, and thereafter describe future therapeutic approaches directed at these receptors. We propose that targeting these receptors will yield effective and better tolerated treatments for Graves' disease, especially for GO. © Georg Thieme Verlag KG Stuttgart · New York.
    No preview · Article · Jul 2015 · Hormone and Metabolic Research
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