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].)

The osteoclast's bone resorptive cycle. (a) The osteoclast, when unattached to bone, is a non-polarized polykaryon with fibrillar actin (red material) diffusely distributed throughout the cell. (b) Upon attachment to bone the actin cytoskeleton forms a ring, or sealing zone, which isolates the resorptive microenvironment from the general extracellular space. (c) At the same time, acidifying vesicles polarize and insert into the plasma membrane juxtaposed to bone to generate the cell's resorptive organelle, the ruffled membrane. (d) The polarized osteoclast secretes hydrochloric acid (HCL), which acidifies the resorptive microenvironment, leading to mobilization of the mineral phase of bone. The exposed organic matrix is then degraded by cathepsin K (Cath K). Having resorbed the underlying bone to a depth of about 50 μm, the osteoclast detaches, disassembles its actin ring and ruffled membrane, and migrates to its next site of resorption.