Gene expression profiling of orbital adipose tissue from patients with Graves' ophthalmopathy: A potential role for secreted frizzled-related protein-1 in orbital adipogenesis

Context: The signs and symptoms of Graves' ophthalmopathy (GO) result from inflammation and increased volume of the orbital adipose tissues and extraocular muscles. Objective: Our objective was to identify differentially regulated genes that may be involved in stimulating the orbital adipose tissue expansion seen in GO. Design: Gene expression profiling was used to compare genes expressed in orbital adipose tissues from GO patients and normal individuals. Setting: The study took place at a private practice tertiary referral center. Patients: Orbital adipose tissues were collected at transantral orbital decompression surgery from 20 euthyroid patients undergoing this procedure for severe GO and at early autopsy from eight normal individuals having no evidence of thyroid or ocular disease. Results: Of the 12,686 genes analyzed, 25 known genes were increased in expression (>4-fold) in GO orbital tissues, whereas 11 genes were decreased (>4-fold). Up-regulated genes, confirmed by quantitative RT-PCR, included secreted frizzled-related protein-1 (sFRP-1; 18.5-fold) and several adipocyte-related genes, including peroxisome proliferator activated receptor-γ(44.1-fold) and adiponectin (25-fold). Treatment in vitro of GO orbital preadipocytes with recombinant sFRP-1 (100 nM) significantly increased adiponectin (2.0-fold; P < 0.05), leptin (7-fold; P < 0.002), and TSH receptor mRNA (13-fold; P < 0.003) levels and enhanced Oil red-O staining in the cultures. Conclusions: These results support the concept that orbital adipogenesis is enhanced in GO and suggest that elevated levels of sFRP-1 in the GO orbit may be involved in stimulating this pathogenic process.