Titanium particles induce chemokine expression in human osteoblasts by a NF-kappaB-mediated mechanism: Possible role for osteoblasts in periprosthetic inflammation

Particulate wear debris is generated continuously within the bone-prosthesis microenvironment by normal wear and corrosion of orthopedic implants. Particulates result in the persistent activation of a variety of cell types in the periprosthetic region, which leads to chronic inflammation and development of osteolysis. Particulate-induced osteolysis is the major contributing factor in premature implant failure in 10–20% of total joint arthroplasties. Osteoblasts are the bone cells responsible for bone formation, which is critical for the osseointegration of the implant. Osteoblasts are adjacent to prosthetic components and continually exposed to particulate species. Osteoblasts are also the primary and essential regulators of osteoclastogenesis, governing the activation of osteolcast bone resorption.; In elucidation of a potential mechanism by which inflammatory cells are recruited to the periprosthectic space by particulate wear debris generation, these studies examined the osteoblast chemokine response to titanium (Ti) particulates. Chemokines function in the chemotaxis of specific cell subpopulations to the site of inflammation. My studies demonstrate enhanced IL-8 and MCP-1 chemokine gene activation in bone marrow derived osteoblasts and MG-63 osteoblastic cells. The osteoblast response was selective for IL-8 and MCP-1, as other chemokine genes were not induced. Ti particle-induced chemokine activation was dependent on both time and concentration of particle exposure, and regulated at the level of gene transcription by the pro-inflammatory transcription factor NF-κB.; Investigation of the NF-κB signaling network demonstrated that Ti particles lead to increased osteoblast chemokine expression via IκBα degradation and a possible secondary pathway independent of IκBα proteolysis. NF-κB is a redox-regulated transcription factor induced by oxidant-mediated stimuli, and IL-8 and MCP-1 are redox-responsive genes. Reactive oxygen species (ROS) are complexed to implant materials in vivo. My studies demonstrate that oxidant signaling may be responsible for Ti particle induction of NF-κB activity and IL-8 chemokine expression. Additionally, MAPK signaling, identified in the upstream activation of NF-κB, is induced by Ti particles in MG-63 cells. Collectively, these studies show that osteoblasts, following particulate challenge, enhance pro-inflammatory chemokine secretion via activation of NF-κB-mediated gene expression. Osteoblasts may actively recruit inflammatory cells to the bone-implant interface aiding in the initiation or exacerbation of periprosthetic inflammation and osteolysis.