title: TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: 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.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Krieger
authors.affiliation: 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.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Place
authors.affiliation: 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.
authors.forename: Carmine
authors.initials: C
authors.lastname: Bevilacqua
authors.affiliation: 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.
authors.forename: Bernice
authors.initials: B
authors.lastname: Marcus-Samuels
authors.affiliation: 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.
authors.forename: Brent S
authors.initials: BS
authors.lastname: Abel
authors.affiliation: 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.
authors.forename: Monica C
authors.initials: MC
authors.lastname: Skarulis
authors.affiliation: 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.
authors.forename: George J
authors.initials: GJ
authors.lastname: Kahaly
authors.affiliation: 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.
authors.forename: Susanne
authors.initials: S
authors.lastname: Neumann
authors.affiliation: 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.
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
mesh_terms: D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D049970:Graves Ophthalmopathy / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D009915:Orbit / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011989:Receptors, Thyrotropin / Q000378:metabolism*
chemical_list: D011989:Receptors, Thyrotropin; D006820:Hyaluronic Acid; D000242:Cyclic AMP; D017526:Receptor, IGF Type 1