Christine C Krieger1, Robert F Place1, Carmine Bevilacqua1, Bernice Marcus-Samuels1, Brent S Abel1, Monica C Skarulis1, George J Kahaly1, Susanne Neumann1, Marvin C Gershengorn1. 1. Laboratory of Endocrinology and Receptor Biology (C.C.K., R.F.P., C.B., B.M.-S., S.N., M.C.G.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Nova Therapeutics LLC (R.F.P.), Pasadena, California; Diabetes, Endocrinology, and Obesity Branch (B.S.A., M.C.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and Johannes Gutenberg University Medical Center (G.J.K.), Mainz, Germany.
Abstract
CONTEXT: The TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role. OBJECTIVE: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. DESIGN/SETTING/PARTICIPANTS: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. MAIN OUTCOME MEASURES: Hyaluronan (hyaluronic acid [HA]) secretion was measured as a major biological response for GOF stimulation. IGF-1R autophosphorylation was used as a measure of direct IGF-1R activation. TSHR activation was determined through cAMP production. RESULTS: A total of 42 out of 57 GO-Ig samples stimulated HA secretion. None of the GO-Ig samples exhibited evidence for IGF-1R autophosphorylation. Both anti-IGF-1R antibodies completely inhibited IGF-1 stimulation of HA secretion. By contrast, only 1 IGF-1R antibody partially blocked HA secretion stimulated by M22 or GO-Igs in a manner similar to linsitinib, whereas the other IGF-1R antibody had no effect on M22 or GO-Ig stimulation. These findings show that the IGF-1R is involved in GO-Igs stimulation of HA secretion without direct activation of IGF-1R. CONCLUSIONS: IGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk rather than direct binding to IGF-1R, and this cross talk is important in the pathogenesis of GO.
CONTEXT: The TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role. OBJECTIVE: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. DESIGN/SETTING/PARTICIPANTS: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. MAIN OUTCOME MEASURES: Hyaluronan (hyaluronic acid [HA]) secretion was measured as a major biological response for GOF stimulation. IGF-1R autophosphorylation was used as a measure of direct IGF-1R activation. TSHR activation was determined through cAMP production. RESULTS: A total of 42 out of 57 GO-Ig samples stimulated HA secretion. None of the GO-Ig samples exhibited evidence for IGF-1R autophosphorylation. Both anti-IGF-1R antibodies completely inhibited IGF-1 stimulation of HA secretion. By contrast, only 1 IGF-1R antibody partially blocked HA secretion stimulated by M22 or GO-Igs in a manner similar to linsitinib, whereas the other IGF-1R antibody had no effect on M22 or GO-Ig stimulation. These findings show that the IGF-1R is involved in GO-Igs stimulation of HA secretion without direct activation of IGF-1R. CONCLUSIONS:IGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk rather than direct binding to IGF-1R, and this cross talk is important in the pathogenesis of GO.
Authors: Clementine J J van Zeijl; Eric Fliers; Chris J van Koppen; Olga V Surovtseva; Marcel E de Gooyer; Maarten P Mourits; Wilmar M Wiersinga; André M M Miltenburg; Anita Boelen Journal: Thyroid Date: 2010-05 Impact factor: 6.568
Authors: Aimee J Varewijck; Anita Boelen; Steven W J Lamberts; Eric Fliers; Leo J Hofland; Wilmar M Wiersinga; Joseph A M J L Janssen Journal: J Clin Endocrinol Metab Date: 2013-01-07 Impact factor: 5.958
Authors: Clementine J J van Zeijl; Eric Fliers; Chris J van Koppen; Olga V Surovtseva; Marcel E de Gooyer; Maarten P Mourits; Wilmar M Wiersinga; André M M Miltenburg; Anita Boelen Journal: Thyroid Date: 2010-10-18 Impact factor: 6.568