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In-depth studies regarding the pathogenesis underlying aseptic loosening of artificial joints have demonstrated that mononuclear macrophages can produce a large amount of inflammatory factors under wear particles stimulation, which lead to periprosthetic osteolysis. Nuclear factor kappa B (NF-кB) is a key information transfer factor that transfers intracellular and extracellular signal and regulates inflammatory transmitter^[1]. Tsuda et al^[2] found OPG can specifically inhibit osteoblast-like cell formation in the conditioned medium of human embryonic lung fibroblast IMR-90. The present study investigated the molecular biological mechanism of osteolysis induced by titanium wear particles of artificial joint.

RANK is a type I transmembrane protein with a chromosomal location of 18q22.1. After binding to RANK ligand, RANK activated transfers signal to cells to induce osteolysis^[3-4]. Tsuji et al^[5-8] reported that severe osteoporosis would occur in rats lacking RANK ligand, while the osteolytic effects of RANK ligand could not be replicated in RANK gene knock-out rats; OPG is found as an osteoclastogenesis inhibitory factor that can bind to RANK ligand and enhance its biological activity. Lacking OPG leads to severe osteoporosis, fragile bone, and spontaneous fracture. Wright et al^[9-12] reported that severe osteoporosis appeared due to increased osteoblasts in OPG gene knock-out rats at 4 months old. Normal bone reconstruction depends on a dynamic balance of bone absorption and bone formation and this procress is closely related to osteoclast and osteoblast functions. The balance of RANK/OPG determines the balance of two process, bone formation and bone resportion^[13-15]. Results from this study demonstrated that RANK mRNA expression was gradually increased at 4 hours in macrophages of the cleaned titanium wear particles group and maintained at a high level thereafter, and OPG mRNA expression was slightly increased at 8 hours, and then recovered to control level. These findings suggest that cleaned titanium particles stimulation induced an unbanlanced ratio of RANK mRNA to OPG mRNA and over-expressed RANK bound to RANK ligand and promoted osteolysis. No RANK mRNA expression was detected in the LPS group, but OPG mRNA expression was transiently increased at 4 hours. These findings suggest that LPS induces osteolysis not by RANK/OPG signal system.  NF-кB is a key nuclear factor that resides in the eukaryocyte and regulates gene expression of numerous pro-inflammatory cytokines. NF-кB specifically binds to various gene promotors or κB sequence in enhancer regions and produces biological effects, thereby playing an important role in inflammatory reaction and immune response. After cells are stimulated by NF-кB, the release of IκB from the trimer results in the exposure of translocation signal sequence of the p50 subunit and DNA binding site of the p65 subunit, thus this allodimer with NF-кB activity is translocated from cytoplasm to nucleus and binds to NF-κB motif, thereby exerting a transcriptional control role. Sabokbar et al^[16] injected tumor necorsis factor-α into RANK gene knock-out mice and found the expression of tartrate-resistant acid phosphatase-positive cells in the peripheral injection region, indicating that TNF-α is independent of RANK signal pathway and persuming that RANK/OPG signal pathway may not be the only signal pathway that mediates osteolysis. Increasing evidence exists that NF-κB signal pathway participates in osteolysis induced by wear particles of artificial joint. Clohisty et al^[17] recently reported that withdrawal of NF-kB signaling blockade would promote implant particle-induced osteoclastogenesis. Other studies also demonstrated that wear particles-induced bone resorption was inhibited in NF-κB-defficient rats^[18-19]. Inflammatory cytokines, such as TNF-α, IL-1, can respectively bind to osteoblast and its precursor cell surface and initiate NF-κB signal pathway to promote osteoblast production and enhance its bone resorption activity; at the same time, NF-κB can activate the osteolytic activity of osteoblasts by binding to inflammatory factors, such as TNF-α and IL-1. NF-κB/inflammatory osteolytic cytokines signal pathway may be another important mechanism underlying wear particles of artifical joint inducing bone resorption and finally resulting in sterile loosening. Results from this study demonstrated that in the LPS group, NF-κB activity increased at 4 hours, peaked at 8 hours, and maintained at a high level within subsequent 32 hours, which was signficantly higher compared with cleaned titanium particles group (P < 0.01). NF-кB DNA binding activity was slightly increased at 16 and 32 hours in the cleaned titanium particles group, but it was still higher than the normal control group (P < 0.05). These findings indicate that LPS, rather than cleaned titanium particles, induces osteolysis primarily by NF-κB/inflammatory cytokine signal pathway. In the LPS-bound titanium particle group, RANK mRNA increased at 4 hours and was gradually increased thereafter, OPG mRNA expression was transiently increased at 8 hours, NF-κB activity was increased at 4 hours and maintained at a very high level within subsequent 36 hours. These findings suggest that after LPS binding to titanium particles, these two signal mechanisms, RANK/OPG and NF-κB/inflammatory cytokine, have synergistic effects during artificial joint loosening.

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