The role of endogenous glucocorticoids in bone and cartilage destruction by immunologic processes

目前尚不清楚内源性糖皮质激素是否以及如何导致类风湿性关节炎的易感性和严重性。利用免疫炎症的啮齿动物模型，我们最近发现，在某些靶组织中，内源性糖皮质激素作用的关键调节因子11？-羟基类固醇脱氢酶2(11？HSD2)的过度表达可以减轻炎症活动和关节损伤。这些结果有力地表明，受体前代谢和由此产生的局部内源性糖皮质激素浓度在炎症的调节和维持中发挥着重要作用。在目前的提案中，我们打算使用11ç-HSD2转基因和成骨细胞特异性糖皮质激素受体(GR)基因敲除小鼠，结合有效的DNA微阵列方法，在许多不同的自身免疫性关节炎模型中研究这些令人兴奋的形成的机制。本研究的主要目的是确定内源性糖皮质激素在自身免疫性关节炎炎症和骨/软骨损伤中的调节和维持作用。

It is unknown whether and how endogenous glucocorticoids contribute to the susceptibilityand severity of rheumatoid arthritis. Using a rodent model of immune-inflammation, we haverecently discovered that the overexpression of 11 ß-hydroxysteroid dehydrogenase type 2(11ß-HSD2), a key regulator of endogenous glucocorticoid action in certain target tissues,attenuates inflammatory activity and joint damage. These results strongly indicate that bothpre-receptor metabolism and the resulting local concentrations of endogenous glucocorticoidsplay an essential role in the regulation and maintenance of inflammation. In the presentproposal we intend to investigate the mechanisms underlying these exciting fmdings in anumber of different models of auto-immune arthritis, using both 11 ß-HSD2 transgenic andosteoblast-specific Gluococorticoid Receptor (GR) knock-out mice in combination with avalidated DNA microarray approach. The overarching aim of this proposal is to establish therole of endogenous glucocorticoids in mediating, regulating and maintaining inflammationand bone/cartilage destmction in autoimmune arthritis.