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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    • "Unfortunately, the current lack of an effective animal model displaying the known characteristics of TAO represents a fundamental limitation in this field of research. A number of studies have examined the cellular characteristics of orbital fibroblasts cultured from primary cells obtained in TAO patients,36, 37, 38 but results from these in vitro studies should be interpreted with caution when applied toward any clinical investigation. However, our experimental model using a primary cell culture system could be a preliminary step for investigating the cellular effects of potential therapies to be developed for the treatment of TAO disease. "
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    ABSTRACT: The aim of the present study was to identify a new candidate anti-inflammatory compound for use in the active stage of thyroid-associated ophthalmopathy (TAO). Benzylideneacetophenone compound JC3 [(2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one] was synthesized based on a structural modification of yakuchinone B, a constituent of the seeds of Alpinia oxyphylla, which belongs to the ginger family (Zingiberaceae), has been widely used in folk medicine as an anti-inflammatory phytochemical. Orbital fibroblasts were primarily cultured from patients with TAO, and the potential of JC3 to suppress the interferon (IFN)-γ-induced protein (IP)-10/CXCL10 production in these cells was determined. IFN-γ strongly increased the level of IP-10/CXCL10 in orbital fibroblasts from patients with TAO. JC3 exerted a significant inhibitory effect on the IFN-γ-induced increase in IP-10/CXCL10 in a dose-dependent manner; its potency was greater than that of an identical concentration of yakuchinone B with no toxicity to cells at the concentration range used. Moreover, the constructed dimer and trimer polystructures of JC3, showed greater potency than JC3 in suppressing the IFN-γ-induced production of IP-10/CXCL10. JC3 significantly attenuated the IP-10/CXCL10 mRNA expression induced by IFN-γ, and a gel-shift assay showed that JC3 suppressed IFN-γ-induced DNA binding of signal transducer and activator of transcription-1 (STAT-1) in TAO orbital fibroblasts. Our results provide initial evidence that the JC3 compound reduces the levels of IP-10/CXCL10 protein and mRNA induced by IFN-γ in orbital fibroblasts of TAO patients. Therefore, JC3 might be considered as a future candidate for therapeutic application in TAO that exerts its effects by modulating the pathogenic mechanisms in orbital fibroblasts.
    Experimental and Molecular Medicine 06/2014; 46(6):e100. DOI:10.1038/emm.2014.26 · 3.45 Impact Factor
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    • "Treg cells from patients with Graves’ ophthalmopathy showed different immunomodulation response compared with normal controls [10]. In addition, orbital fibroblasts express CD40, ICAM, IGF-1R, and other immunomodulatory molecules, amplifying the immune response [4,11,12]. "
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    ABSTRACT: Abstract Graves' ophthalmopathy is an inflammatory autoimmune disease of the orbit, characterized by inflammation and proliferation of the orbital tissue caused by CD4+T cells and orbital fibroblasts. Despite recent substantial findings regarding its cellular and molecular foundations, the pathogenesis of Graves' ophthalmopathy remains unclear. Accumulating data suggest that microRNAs play important roles in the pathophysiology of autoimmunity and proliferation. Specifically, microRNA-155 (miR-155) can promote autoimmune inflammation by enhancing inflammatory T cell development. In contrast to miR-155, microRNA-146a (miR-146a) can inhibit the immune response by suppressing T cell activation. Furthermore, miR-155 and miR-146a are involved in cell proliferation, differentiation, and many other life processes. Thus, miR-155 and miR-146a, with opposite impacts on inflammatory responses carried out by T lymphocytes, appear to have multiple targets in the pathogenesis of Graves' ophthalmopathy. Our previous work showed that the expression of miR-146a was significantly decreased in peripheral blood mononuclear cells from Graves' ophthalmopathy patients compared with normal subjects. Accordingly, we proposed that the expression of miR-155 increased and the expression of miR-146a decreased in the target cells (CD4+T cells and orbital fibroblasts), thus promoting ocular inflammation and proliferation in Graves' ophthalmopathy. The proposed hypothesis warrants further investigation of the function of the differentially expressed microRNAs, which may shed new light on the pathogenesis of Graves' ophthalmopathy and lead to new strategies for its management.
    Medical science monitor: international medical journal of experimental and clinical research 04/2014; 20:639-43. DOI:10.12659/MSM.890686 · 1.43 Impact Factor
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    ABSTRACT: Mild to moderate forms of orbitopathy are common in auto-immune thyroid diseases, whereas severe forms are rare. Euthyroidism restoration, no smoking, and ocular local lubricants are necessary for all the patients. In case of mild orbitopathy, treatment by selenium is now indicated. Active forms of thyroid orbitopathy are better treated by IV steroids. Surgery is indicated in optic neuropathy resistant to steroids and in sequellar forms of the disease.
    Revue médicale suisse 01/2013; 9(368):66-71.
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