Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves鈥?orbitopathy

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• 作者：Terry J. Smith ; M.D.^a ; ^b ; ^e ; ^{terrysmi@med.umich.edu} (Frederick G.L. Huetwell ; Professor of Ophthalmology ; Visual Sciences ; Professor of Internal Medicine ; Guest Professor) ; Laszlo Hegedü ; s ; M.D. ; DMSc^c ; ^d (Professor of Internal Medicine ; Endocrinology ; Senior Consultant Physician) ; Raymond S. Douglas ; M.D. ; Ph.D.^a ; ^e (Associate Professor of Ophthalmology ; Visual Sciences ; Director)
• 关键词：Graves&rsquo ; ophthalmopathy ; TSH receptor ; IGF-1 receptor ; orbital fibroblast ; fibrocyte
• 刊名：Best Practice Research Clinical Endocrinology Metabolism
• 出版年：2012
• 期刊代码：34_1521690X
• 类别：med
• 出版时间：June, 2012
• 卷：26
• 期：3
• 页码：291-302
• 文件大小：433 K

摘要

The etiology of Graves鈥?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鈥?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 鈥減artners in crime鈥? Involvement of the former probably transcends disease boundaries, while TSHR may not.