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Overexpression of Immediate Early Genes in Active Graves’ Ophthalmopathy

Department of Endocrinology (M.L., T.V., H.P., M.R., L.G., B.H.), and Departments of Ophthalmology (C.F., P.A.) and Plastic Surgery (M.A.), Malmö University Hospital, S-205 02 Malmö, Sweden

Address all correspondence and requests for reprints to: Mikael Lantz, M.D., Ph.D., Department of Endocrinology, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail: mikael.lantz{at}endo.mas.lu.se.

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-1ß, 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-1ß, 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.

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