Development of osteoporosis severely complicates long-term glucocorticoid (GC) therapy. Using a Cre-transgenic mouse line, we now demonstrate that GCs are unable to repress bone formation in the absence of glucocorticoid receptor (GR) expression in osteoblasts as they become refractory to hormone-induced apoptosis, inhibition of proliferation, and differentiation. In contrast, GC treatment still reduces bone formation in mice carrying a mutation that only disrupts GR dimerization, resulting in bone loss in vivo, enhanced apoptosis, and suppressed differentiation in vitro. The inhibitory GC effects on osteoblasts can be explained by a mechanism involving suppression of cytokines, such as interleukin 11, via interaction of the monomeric GR with AP-1, but not NF-kappaB. Thus, GCs inhibit cytokines independent of GR dimerization and thereby attenuate osteoblast differentiation, which accounts, in part, for bone loss during GC therapy.

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Cartilage and bone are severely affected by glucocorticoids (GCs), steroid hormones that are frequently used to treat inflammatory diseases. Major complications associated with long-term steroid therapy include impairment of cartilaginous bone growth and GC-induced osteoporosis. Particularly in arthritis, GC application can increase joint and bone damage. Contrarily, endogenous GC release supports cartilage and bone integrity. In the last decade, substantial progress in the understanding of the molecular mechanisms of GC action has been gained through genome-wide binding studies of the GC receptor. These genomic approaches have revolutionized our understanding of gene regulation by ligand-induced transcription factors in general. Furthermore, specific inactivation of GC signaling and the GC receptor in bone and cartilage cells of rodent models has enabled the cell-specific effects of GCs in normal tissue homeostasis, inflammatory bone diseases, and GC-induced osteoporosis to be dissected. In this review, we summarize the current view of GC action in cartilage and bone. We further discuss future research directions in the context of new concepts for optimized steroid therapies with less detrimental effects on bone.

Despite several side effects, glucocorticoids (GCs) have been widely used for 60 y to treat rheumatoid arthritis on the basis of their antiinflammatory effects. However, the cells targeted by GCs and the transcriptional mechanisms underlying their actions through the glucocorticoid receptor (GR) in steroid therapy remain poorly defined. Using cell type-specific GR-deficient mice subjected to antigen-induced arthritis (AIA) as a model of human rheumatoid arthritis, we show that GC action on T cells but not myeloid cells is critical for therapeutic intervention in AIA. Furthermore, the resistance of mice expressing a DNA binding-defective GR (GR dim ) to GC treatment reveals that dimerization of the GR is indispensable for the antiinflammatory effects. In these mice, the GC-induced suppression of T H 1 and T H 17 cell-derived proinflammatory cytokines is impaired. Our finding that IL-17A −/− mice are resistant to GC therapy, whereas IFN-γ −/− mice respond as efficiently as WT mice implies that IL-17-producing T cells and not IFN-γ-producing T cells are the most important targets for an efficient GC therapy. The present study's identification of the critical cell type and the mode of GR action in steroid therapy of AIA significantly advances our understanding of steroid therapy and should lead to therapies with greater efficiency and fewer side effects.conditional knockout mice | activated T cells | corticosteroid therapy | chronic inflammation