Table 2. Role of key inflammatory mediators contributing to osteolysis.
| Molecular effector | Role | Comments |
|---|---|---|
| TNF-α | Increases RANKL expression54 Strongly augments RANKL-induced osteoclastogenesis55 Independently activates osteoclasts with similar potency of RANKL; augments RANKL-induced activation58 Inhibits osteoclast apoptosis by Akt and ERK phosphorylation59 Strongly suppresses procollagen 1 expression101 Increases IL-1 and IL-1R type I expression in vitro60 Enhances macrophage-attractant chemokine production110 | |
| IL-1 | Increases RANKL expression54 Inhibits osteoclast apoptosis59 Mediates TNF-α-induced RANKL expression60 Enhances osteoclastogenesis in presence of RANKL60 Capable of activating MAPK and NF-κB48 | |
| IL-6 | Secreted by osteoblasts in response to wear particle, IL-1β, and TNF-α stimulation6 Secretion induced by NF-κB activation7 Released by stimulated macrophages and associated with increased osteolysis7,31 Stimulates RANKL expression on osteoblast cell surface in inflammatory state111 | |
| IL-18 | Activates MAPK48 | |
| RANKL | Inhibits osteoclast apoptosis59 | |
| NALP3 inflammasome | Activated by cathepsin,7,44 and ROS, in conjunction with other intracellular danger signals (ATP, K+, urate, etc.)7,48,50,51 Complexes with PYCARD, leading to caspase-1 recruitment and activation4,7,44,48–50 | Activation occurs through nonspecific danger signals |
| Caspase-1 | Regulator of inflammation and cell survival and differentiation48 Cleaves pro-IL-1β and pro-IL-18 into active forms, allowing for their secretion4,7,44,48–50 Increased levels, along with IL-1β and IL-18, after in vitro treatment of DCs with UHMWPE; this response diminished with cathepsin inhibition44 | |
| TLR | Activated by DAMPs released in tissue damage7,47 TLR2 and 1/2 activated by UHMWPE alkane polymers with a 12–16 carbon length46 Activation by alkane polymers enhanced by polymer oxidative damage up to 140-fold46 Stimulation ultimately leads to DC, monocyte, macrophage, and osteoclast activation, with upregulation of MHC-II, B7–1, B7–2, CD40, IL-1, IL-6, IL-10, IL-12, TNF- α, and IFN-γ, as well as TLR1 and 244 TLRs 2, 4, 5, and 9 observed in monocytes/macrophages of osteolytic tissue in vitro, with TLR2 and 5 response dominant45 TLR9 characterized as strongest promoter of phagocytosis in a bacterial model43 | Taken together, these first four points demonstrate a nonspecific and self-propagating immune response, indicative of the innate immune system |
| Complement | PE activates alternative complement pathway, likely through Factor B112 Complement factors adsorbed to PE particles after activation112 Complement activation enhances vascular permeability, chemotaxis, and phagocytosis112 C3 demonstrates ability to recruit osteoclasts,113 and activate NF-κB40 | Along with TLR, represents early, nonspecific immune response |
| Matrix metalloproteinase (MMP) | MMPs 1, 9, 10, 12, and 13 highly elevated in AL periprosthetic tissue, in addition to lesser elevation of others114 MMPs 1, 2, 3, and 9 identified in macrophages, fibroblasts, and endothelial cells of AL periprosthetic tissue115 | Combined action capable of degrading almost all elements of periprosthetic extracellular matrix114 |
| MAPK | Activated by TNF-α, IL-1, and IL-1848,60 Signaling leads to IL-1 and other cytokine expression, as well as NF-κB activation48,60 |
DAMP, damage-associated molecular pattern; DC, dendritic cell; IL-1, interleukin-1; IFN-γ, interferon-γ; MHC-II, major histocompatibility complex class II; PE, polyethylene; RANKL, receptor activator of nuclear factor-κB ligand; ROS, reactive oxygen species; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α; UHMWPE, ultra-high molecular weight polyethylene.