title: Locally produced insulin-like growth factor-1 by orbital fibroblasts as implicative pathogenic factor rather than systemically circulated IGF-1 for patients with thyroid-associated ophthalmopathy.
abstract: BACKGROUND
  To determine the correlation between clinical activity scores (CAS) of thyroid-associated ophthalmology (TAO) patients and their locally produced and/or systemically circulating insulin-like growth factor-1 (IGF-1), and to assess the possible pathogenic role of IGF-1 in TAO.
  
  
  METHODS
  Eighteen patients with TAO, and 16 age- and gender-matched controls were included in the present study. Among them, orbital tissue surgically collected from five TAO patients and five healthy controls was used for orbital fibroblasts (OFs) culture and in vitro study. Total and free IGF-1 in serum levels were determined by an ELISA kit for all the participants in this study. The IGF-1 concentration in culture media of OFs was determined using a noncompetitive time-resolved radioimmunoassay kit. The effect of octreotide (OCT), a somatostatin analog, on proliferation of OFs was assessed using the MTT assay. IGF-1 mRNA levels were measured by real-time polymerase chain reaction (PCR).
  
  
  RESULTS
  Cultured OFs from both TAO patients and normal donors secreted IGF-1, and the secretion continued over a 72 hour period in vitro. IGF-1 secretion by OFs was elevated in the TAO group. Both the elevated secretion of IGF-1 and proliferation of OFs from TAO patients could be inhibited by OCT. Result of quantitative PCR showed that IGF-1 mRNA expression by OFs in TAO patients was up-regulated more than 2-fold compared with normal controls (P < 0.05), and this up-regulation was prevented by OCT treatment. Total and free serum IGF-1 levels in TAO patients were similar to those of normal controls. However, the IGF-1 level in cultured medium of OFs from TAO patients, but not serum levels of IGF-1, was positively correlated with CAS (r = 0.97, P = 0.017).
  
  
  CONCLUSIONS
  Local production of IGF-1 by cultured OFs may be positively correlated with CAS, whereas systemically circulating IGF-1 may remain unchanged in TAO patients. Thus, locally produced IGF-1 may develop a role in the pathogenesis of TAO in an autocrine or paracrine fashion. The inhibitory effect of OCT on proliferating and IGF-1 mRNA levels of cultured OFs from TAO patients may be used as the mechanistic explanation for somatostatin analog as a valuable option in the treatment of TAO.
authors.affiliation: The F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
authors.forename: Delu
authors.initials: D
authors.lastname: Song
authors.forename: Renyan
authors.initials: R
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhong
authors.forename: Weiye
authors.initials: W
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Fangtian
authors.initials: F
authors.lastname: Dong
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015200:Fluoroimmunoassay; D049970:Graves Ophthalmopathy / Q000097:blood* / Q000209:etiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015282:Octreotide / Q000494:pharmacology; D009915:Orbit / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D015282:Octreotide