抄録
Steroid-induced osteoporosis is the most common form of secondary osteoporosis. The mechanisms of glucocorticoid (GC)-induced osteoporosis may be divided into indirect and direct effects. A putative indirect mechanism of GC-induced osteoporosis is thought to be secondary hyperparathyroidism or estrogen deficiency. Recent studies, however, suggest that the direct action of GC on bone metabolism is more important. GC stimulates the expression of the receptor activator of NF-κB ligand (RANKL) and inhibits osteoprotegerin (OPG) expression in a dose-dependent manner in human osteoblasts. The resultant increase in the RANKL:OPG ratio results in the induction of osteoclastogenesis. GC predominantly inhibits human osteoblast proliferation and enhances the differentiation of human-pre-osteoblasts. GC also acts directly on human osteoblasts to up-regulate the expression of M-CSF which is an essential cytokine for the survival of osteoclast precursors. The addition of GC to the culture of human peripheral blood mononuclear cells (PBMC) results in a marked increase in the formation of osteoclasts and an increase in lacunar resorption. Moreover, GC has been shown to inhibit apoptosis in mouse osteoclasts. In addition, the direct effect of dexamethasone (Dex) upon human osteoclastogenesis from PBMC is mediated via the balance between RANKL and IFN-γ in activated CD4 T cells. Dex induced human osteoclastogenesis without adding osteoblasts or soluble RANKL. Dex dose-dependently increased the ratio of RANKL-positive cells to IFN-γ positive cells (RANKL:IFN-γ ratio) only by reducing IFN-γ-positive cells, suggesting that Dex stimulates osteoclast differentiation by elevating the RANKL:IFN-γ ratio in CD4+ T cells. The balance between RANKL and OPG (RANKL:OPG) or RANKL and IFN-γ (RANKL:IFN-γ) on osteoblasts and T cells may have an important role in GC-induced osteoclastogenesis. Thus, therapeutic modulation of the expression of RANKL, OPG and IFN-γ by osteoblasts and T cells represents a novel strategy to prevent GC-induced osteoporosis.
