Figure 2.

Components of inflammatory response ‘inducers—sensors—mediators—effectors’ potentially associated with periprosthetic osteolysis and aseptic loosening. The host response is initiated by triggers (inducers), which are of both exogenous (wear particles, bacteria or microbial remnants) and endogenous (cells, extracellular matrix and bodily fluids) origin. Wear particles with adsorbed host proteins are phago-/pinocytosed (leading to a foreign body reaction) and sensed by pattern recognizing receptors, such as TLRs and receptor for advanced glycation end products (RAGE). Trauma-associated necrosis leads to the release of cellular components, such as ATP, K⁺ ions, fragmented DNA, members of the S100 calcium-binding protein family, advanced glycation end products (AGE) and others, effectively triggering inflammation after binding to, and activating, respective sensors, such as purinoreceptors, P2X7, NACHT, Leucine-Rich Repeat- and PYD-domains Containing Protein 3 (NALP3 or cryopyrin), high mobility group box 1 protein (HMGB1; the complex with DNA that can stimulate TLR9), RAGE and others, expressed mostly by macrophages. Trauma also leads to the breakdown of extracellular matrix components, such as hyaluronan (HA), fragments of which are sensed by TLRs. Receptors, or sensors, activate macrophages to release the pro-inflammatory factors IL-1, IL-12, IL-18, IL-33, TNF-α, cyclooxygenase 2 (COX-2) and inducible nitric oxide synthetase (iNOS), but also the anti-inflammatory factors IL-10 and TGF-β. IL-6 has multiple activities depending on differentiation and activation status, and receptor expression on target cells, such as osteoclasts; therefore, it could both suppress osteolysis but facilitate osteoclast formation. In addition to the above-mentioned cellular receptors, soluble factors, such as Factor XII, sense extracellular matrix components presented by collagen leading to activation of coagulation, fibrinolysis and complement, which could substantially contribute to the recruitment of inflammatory cells. The above-mentioned inflammatory mediators contribute to the activation or differentiation of several cell lines participating in periprosthetic osteolysis and aseptic loosening of THA. Anti-inflammatory factors associated with bone homeostasis are in blue, pro-inflammatory factors or those associated with bone resorption are in red.