Overexpression of immediate early genes in active Graves' ophthalmopathy

J Clin Endocrinol Metab. 2005 Aug;90(8):4784-91. doi: 10.1210/jc.2004-2275. Epub 2005 May 31.


Context: In Graves' ophthalmopathy a major problem is an increase in the intraorbital adipose tissue volume.

Objective: The aim of this work was to define mechanisms of orbital adipogenesis.

Design: This was an open-label prospective study.

Setting: The study was conducted at the Clinic of Endocrinology, University Hospital.

Participants: The study consisted of patients (n = 5) with severe ophthalmopathy with affection of the optic nerve and thyroid healthy controls (n = 5).

Interventions: We performed lateral decompression of orbital tissue in patients unresponsive to corticosteroids and restorative surgery of the upper eyelid in thyroid healthy controls.

Main outcome measure: We made large-scale measurements of gene expression, with microarray technique based on determination of fluorescence intensities in cases and controls.

Results: A marker of adipose tissue, stearoyl-coenzyme A desaturase, was overexpressed in ophthalmopathy, and selection criteria were set to favor identification of genes known to be expressed in normal adipogenesis. The immediate early gene, cysteine-rich, angiogenic inducer, 61 (CYR61), was overexpressed in addition to 15 other immediate early genes (IEGs), and the expression of selected IEGs was confirmed with RT-PCR: CYR61, cyclooxygenase-2, dual-specificity phosphatase 1, B cell translocation gene 2, and early growth response 1. CYR61-responsive genes, known to participate in inflammation, IL-1beta, matrix metalloproteinase-3, and vascular endothelial growth factor were also overexpressed. Patients showed greater expression of CYR61 in the active than the chronic phase of ophthalmopathy, indicating that CYR61 is a marker of disease activity. Cyclooxygenase-2, the target gene of IL-1beta, was also overexpressed, although all patients had been treated with corticosteroids.

Conclusion: Adipocyte-related IEGs are overexpressed in active ophthalmopathy, and CYR61 may have a role in both orbital inflammation and adipogenesis and serve as a marker of disease activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / pathology
  • Adipose Tissue / physiology
  • Aged
  • Cysteine-Rich Protein 61
  • Eyelids / pathology
  • Eyelids / physiology
  • Female
  • Gene Expression
  • Genes, Immediate-Early / genetics*
  • Graves Disease / genetics*
  • Graves Disease / pathology
  • Graves Disease / physiopathology*
  • Humans
  • Immediate-Early Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / genetics
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis*
  • Orbit
  • Prospective Studies


  • CCN1 protein, human
  • Cysteine-Rich Protein 61
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins