Figure 2

Mechanisms of osteoclastogenesis induced by tumour necrosis factor (TNF)-α/IL-1. TNF-α interacts with its p55 receptor (TNFR) on both marrow stromal cells and osteoclast precursors in the form of marrow macrophages. Activation of the TNFR stimulates the expression of macrophage colony-stimulating factor (M-CSF) by stromal cells, which occupies its receptor, c-Fms, on osteoclast precursors. Signaling through p38 mitogen-activated protein kinase, TNF-α also induces stromal-cell synthesis of IL-1, which upregulates its own functional receptor, IL-1RI. Occupancy of now abundant IL-1RI similarly activates p38, which promotes RANKL production. In macrophages, TNF-α enhances RANK expression and the synthesis of IL-1, whose functional receptor is upregulated by the same three cytokines, also in a p38-dependent manner. Coincidentally, RANKL suppresses the IL-1 decoy receptor IL-1RII. TNF-α-induced IL-1RI upregulation in macrophages occurs by a combination of IL-1-dependent and IL-1-independent mechanisms. IL-1 interacting with its receptor on osteoclast precursors, in conjunction with RANKL and M-CSF, directly induces these cells to commit to the osteoclast phenotype. IL-1 mediates about 50% of the osteoclastogenic effect of TNF-α. (Modified from [80].)