11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates cortisol (F) from cortisone (E). Our recent human studies identified 11beta-HSD1 to the non-pigmented layer (NPE) of the ocular ciliary epithelium, confirming that this enzyme is integral to the physiology of aqueous humour (AH) production vital for the maintenance of intraocular pressure (IOP). 11beta-HSD1 has also been implicated in the pathogenesis of obesity, and our previous data have defined this enzyme in subcutaneous and omental fat. The retro-orbital fat (ROF) depot, located behind the eye, is an important target tissue for orbital inflammatory disease. Detailed evaluation of 11beta-HSD1 activity in the NPE and ROF remains unexplored largely due to inaccessibility of human tissue. Animal models are essential for further evaluation of ocular and orbital 11beta-HSD1, the most appropriate model appears to be the New Zealand White Albino Rabbit (NZWAR).
11beta-HSD1 immunohistochemical analyses of three NZWAR, confirmed expression to the NPE layer of the cilary body. 11beta-HSD1 enzyme assays on intact ciliary body tissue revealed predominant oxo-reductase (E to F) activity. This was supported by a high F:E ratio in AH (2.67 (1.25-5.2)median (range)) versus plasma 11.25 (10-12.5). These results endorse our human studies which suggest that modulation of AH production by 11beta-HSD1 is important in the regulation of IOP.
In addition, we have defined expression of 11beta-HSD1 to ROF. Primary cultures demonstrated abundant oxo-reductase activity compared with paired omental fat. This may well have important implications in differentiation, proliferation and inflammatory infiltration of this fat pad, in conditions such as thyroid eye disease. As T3 regulates 11beta-HSD1 activity, it is possible that manipulation of this isozyme could provide a novel pharmacological form of orbital decompression.
These data suggest that the NZWAR is a suitable model for evaluating 11beta-HSD1 activity in ocular and orbital tissues.
22 - 24 Mar 2004
British Endocrine Societies