Wear particles directly or indirectly activate NF-κB upstream including the TNF-α receptor (TNFR), IL-1 receptor (IL1R), and toll-like receptor (TLR) in macrophages. The activation of NF-κB enhances the expression of chemokines, RANKL, and proteinases that lead to osteolysis via different mechanisms (green boxes). Chemokines recruit macrophages, osteoprogenitor cells, and mesenchymal stem cells (MSC), whereas RANKL induces the maturation of osteoclasts. Suppression of NF-κB activation can be achieved by targeting 1) upstream activators; 2) IκB; 3) IKK kinase; 4) the core component of NF-κB (RelA/p50); or 5) nuclear translocation and DNA binding ability of NF-κB. Notably, the NF-κB downstream target genes may also affect osteoblasts and MSCs (pink box).