Overexpression of immediate early genes in active Graves' ophthalmopathy.
BACKGROUND
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.


METHODS
This was an open-label prospective study.


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


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


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


METHODS
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.


CONCLUSIONS
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.
Lantz
Mikael
M
Department of Endocrinology, Malmö University Hospital, S-205 02 Malmö, Sweden. mikael.lantz@endo.mas.lu.se
Vondrichova
Tereza
T
Parikh
Hemang
H
Frenander
Christofer
C
Ridderstråle
Martin
M
Asman
Peter
P
Aberg
Magnus
M
Groop
Leif
L
Hallengren
Bengt
B
D000273:Adipose Tissue / Q000473:pathology / Q000502:physiology; D000368:Aged; D055515:Cysteine-Rich Protein 61; D005143:Eyelids / Q000473:pathology / Q000502:physiology; D005260:Female; D015870:Gene Expression; D017781:Genes, Immediate-Early / Q000235:genetics*; D006111:Graves Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D009915:Orbit; D011446:Prospective Studies
C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins