title: Bidirectional TSH and IGF-1 receptor cross talk mediates stimulation of hyaluronan secretion by Graves' disease immunoglobins.
abstract: BACKGROUND
  There is no pathogenetically linked medical therapy for Graves' ophthalmopathy (GO). Lack of animal models and conflicting in vitro studies have hindered the development of such therapy. Recent reports propose that Graves' Igs bind to and activate thyrotropin receptors (TSHRs) and IGF-1 receptors (IGF-1Rs) on cells in orbital fat, stimulating hyaluronan (HA) secretion, a component of GO.
  
  
  OBJECTIVE
  The objective of the study was to investigate potential cross talk between TSHRs and IGF-1Rs in the pathogenesis of GO using a sensitive HA assay.
  
  
  METHODS
  Orbital fibroblasts from GO patients were collected in an academic clinical practice and cultured in a research laboratory. Cells were treated with TSH, IGF-1, and a monoclonal Graves' Ig M22.
  
  
  METHODS
  HA was measured by a modified ELISA.
  
  
  RESULTS
  Simultaneous activation by TSH and IGF-1 synergistically increased HA secretion from 320 ± 52 for TSH and 430 ± 65 μg/mL for IGF-1 alone, to 1300 ± 95 μg/mL. IGF-1 shifted the TSH EC50 19-fold to higher potency. The dose response to M22 was biphasic. An IGF-1R antagonist inhibited the higher potency phase but had no effect on the lower potency phase. M22 did not cause IGF-1R autophosphorylation. A TSHR antagonist abolished both phases of M22-stimulated HA secretion.
  
  
  CONCLUSIONS
  M22 stimulation of HA secretion by GO fibroblasts/preadipocytes involves cross talk between TSHR and IGF-1R. This cross talk relies on TSHR activation rather than direct activation of IGF-1R and leads to synergistic stimulation of HA secretion. These data propose a model for GO pathogenesis that explains previous contradictory results and argues for TSHR as the primary therapeutic target for GO.
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-8029.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Krieger
authors.forename: Susanne
authors.initials: S
authors.lastname: Neumann
authors.forename: Robert F
authors.initials: RF
authors.lastname: Place
authors.forename: Bernice
authors.initials: B
authors.lastname: Marcus-Samuels
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
mesh_terms: D002478:Cells, Cultured; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006111:Graves Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D007136:Immunoglobulins / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009915:Orbit / Q000473:pathology; D020239:Receptor Cross-Talk / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D011989:Receptors, Thyrotropin / Q000502:physiology*; D013972:Thyrotropin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007136:Immunoglobulins; D011989:Receptors, Thyrotropin; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D006820:Hyaluronic Acid; D017526:Receptor, IGF Type 1