Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves' orbitopathy.
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.
University of Michigan Medical School, Ann Arbor, MI 48105, USA. terrysmi@med.umich.edu
Terry J
TJ
Smith
Laszlo
L
Hegedüs
Raymond S
RS
Douglas
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D049970:Graves Ophthalmopathy / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D018828:Immunoglobulins, Thyroid-Stimulating / Q000032:analysis; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009915:Orbit / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013961:Thyroid Gland / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018828:Immunoglobulins, Thyroid-Stimulating; D011989:Receptors, Thyrotropin; C094372:thyrotropin-binding inhibitory immunoglobulin; D007334:Insulin-Like Growth Factor I; D006820:Hyaluronic Acid; D017526:Receptor, IGF Type 1