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Interactions between Glucocorticoids and Cytokines in the Bone Microenvironment

Abstract: Cytokines belonging to the so‐called interleukin‐6 (IL‐6) or gp130 cytokine family, notably IL‐6 and IL‐11, are known as pro‐resorptive cytokines, in that they promote osteoclastogenesis. Glucocorticoid (GC)‐induced osteoporosis is admittedly the most frequent secondary osteoporosis. The pathogenesis still has many unresolved issues. Although the effects of GCs on cytokine production and recognition have been extensively studied, little is known about the effects of cytokines on GC action at the target level. We have focused on the effects of IL‐6 and IL‐11 on specific binding by type II GC receptors (GRs) in two human osteoblast‐like cell lines (Saos‐2 and MG‐63) that have remarkably different constitutive expression of these cytokines and GRs as well. We have provided evidence that IL‐6 upregulates GR binding sites, while IL‐11 downregulates these sites, as determined by radioligand binding assay and Scatchard analysis. GR affinity (Kd) did not change after exposure to both cytokines. A number of experiments were consistent with the view that in human osteoblast‐like cells, cytokines of the IL‐6 family have autocrine modulatory effects on GRα (GRβ is a variant that does not bind specifically in our method). Complex effects of GCs on the system(s) of proinflammatory/anti‐inflammatory cytokines and conversely of these cytokines on GC action could account for the dynamics of bone loss in patients given GCs and conceivably having high concentrations of these cytokines in the bone microenvironment.