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Ajay E. Kuriyan, Geniece M. Lehmann, Charles E. O'Loughlin, Steven E. Feldon, Richard P. Phipps; Orbital Fibroblasts From Thyroid Eye Disease Patients Differ In Proliferative And Adipogenic Responses Depending On Disease Sub-type. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5105.
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Thyroid Eye Disease (TED) is an autoimmune process primarily associated with Graves’ Disease. Imaging is used to classify patients into 2 groups: Type I with expansion of the fat compartment and Type II with enlargement of the extraocular muscles. Some patients have both components. We tested the hypothesis that orbital fibroblasts (OFs) from Type I TED are prone to adipogenesis, whereas OFs from Type II TED are prone to proliferation. We also examined the ability of agents to inhibit OF adipogenesis and proliferation.
CT scans and tissue samples were obtained from TED and non-TED patients undergoing orbital surgery at the Flaum Eye Institute. OFs from 3 Type I, 3 Type II, and 2-3 non-TED patients were treated with 5ng/ml transforming growth factor beta (TGFB), 10% fetal bovine serum (FBS), co-culture with autologous T-cells, 10υM pioglitazone, or 10υM 15d-prostaglandin J2 (15d-PGJ2). To assess the effects of treatment agents, OFs were also co-treated with TGFB or 15d-PGJ2 and 10nM dexamethasone, 10υmol/L NS398 (Cox-2 inhibitor), or 20υmol/L indomethacin (Cox-1 and Cox-2 inhibitor). Proliferation and adipogenesis were measured using the tritiated thymidine assay after 72 hr and the AdipoRed assay after 8 d, respectively. A mixed-effects model was used to compare proliferation and adipogenesis of OFs from different patients. One-way ANOVA with Tukey analysis was used to compare the effect of treatments on adipogenesis and proliferation.
There was a trend toward more proliferation in Type II OFs compared to Type I OFs with autologous T-cell co-culture (P=0.0633). Type II OFs proliferated more with 5ng/ml TGFB (P<0.0001) and 10% FBS (P<0.0001) than Type I OFs. Type I OFs had more adipogenesis than Type II OFs with 5υM 15d-PGJ2 (P=0.0259) and 10υM pioglitazone (P=0.006) treatments. Indomethacin inhibited TGFB-induced proliferation in Type I (P<0.001) and II (P<0.001) OFs and 15d-PGJ2-induced adipogenesis in Type I OFs (P<0.01).
Type II OFs were driven to proliferate more than Type I OFs, while Type I OFs were driven to adipogenesis more than Type II OFs. This study demonstrates the heterogeneity of OFs from Type I and Type II TED patients. Indomethacin is a potent inhibitor of proliferation and adipogenesis in OFs. Further investigation is required to determine if factors that influence the fate of TED OFs are genetic, environmental, or a combination of the two. Future studies investigating the role of indomethacin in TED are warranted.
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