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O. M. Durrani, C. U. Onyimba, I. J. Bujalska, J. Abbott, P. Tomlins, T. T. Q. Reuser, G. E. Rose, J. W. Tomlinson, E. A. Walker, S. Rauz; Thyroid Associated Ophthalmopathy - Cushing’s Disease of the Orbit?. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3573.
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Thyroid-associated ophthalmopathy (TAO) is a sight-threatening autoimmune disease. The clinical features are explained by increased intraorbital volume secondary to inflammatory cell infiltration and tissue-matrix remodelling where adipogenesis has been identified as a fundamental pathogenic mechanism. 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) increases cortisol bioavailability and is pivotal in mediating glucocorticoid (GC) responses in adipose tissue and inflammation. In this study we characterise 11ß-HSD1 as a determinant of the adipogenic pathways in TAO orbital fat (OF) compared to control OF.
OF was harvested from 38 clinically inactive TAO and 43 control patients undergoing orbital surgery. GC-mediated adipogenic and inflammatory pathways were examined by a combination of immunohistochemistry, primary preadipocyte cultures, specific enzyme assays, real-time RT-PCR, and colorimetric proliferation assays.
Histomorphometric analyses of fixed adipose tissue defined smaller TAO adipocytes compared with controls. Primary cultures of TAO OF preadipocytes demonstrated higher 11ß-HSD1 oxo-reductase activity generating cortisol compared to control OF preadipocytes (p<0.05) which was potently regulated by pro-inflammatory cytokines. These results were supported by a greater mRNA expression for 11ß-HSD1 and its regulatory enzyme (hexose-6-phosphate-dehydrogenase) in TAO whole adipose tissue (p<0.05). Expression of glucocorticoid receptor-α mRNA, fatty acid binding protein 4 (marker of adipocyte differentiation) and inflammatory cytokines (IL-1ß, IL-6, TNF-α, TGF-ß2) were significantly higher in TAO OF compared with control OF (p<0.05). Functional studies revealed OF preadipocyte proliferation was regulated by 11ß-HSD1.
TAO adipocytes are more differentiated and express higher levels of 11ß-HSD1 compared to control OF, whilst local amplification of cortisol increases preadipocyte proliferation. These data suggest that 11ß-HSD1 is a critical determinant of the adipogenic pathways in the TAO OF microenvironment.
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