Molecular determinants of glucocorticoid actions in inflammatory joint diseases

• Glucocorticoids (GCs) suppress inflammation in rheumatoid arthritis (RA), but harm bone.
• GC receptor (GR) dimerization contributes to anti-inflammatory action of GCs.
• T cell activation is a major Achilles heel affected by GCs in certain models of arthritis.
• GR monomer interference of AP-1 in osteoblasts is sufficient to contribute to bone loss.
• Selective ligands that do not affect AP-1 interference in bone cells protect bone.

Since their discovery in 1948, glucocorticoids have been widely used clinically to treat inflammatory disorders like rheumatoid arthritis. However, their usefulness, especially in rheumatoid arthritis therapy, is hampered by severe side effects on bone leading to glucocorticoid-induced osteoporosis. The molecular and cellular mechanisms mediating the beneficial and adverse effects remain poorly understood. Nevertheless, advanced molecular biological analyses and in vivo approaches using conditional mutant mice have helped to unravel in part the underlying mechanisms of immunosuppression and side effects of glucocorticoid therapy in arthritis, thereby contributing to an improved understanding of these therapeutically important hormones.