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

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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.