Tumor Necrosis Factor-α Mediates Orthopedic Implant Osteolysis

Abstract

Osteolysis complicating arthroplasty reflects progressive generation of implant-derived wear particles, which prompt an inflammatory reaction attended by recruitment of osteoclasts to the prosthesis-bone interface. To identify a soluble mediator of periprosthetic osteolysis we first showed that implant particles induce c-src in murine bone marrow macrophages (BMMs), a protein specifically expressed when these cells commit to the osteoclast phenotype. The fact that tumor necrosis factor-alpha (TNF) is a potent osteoclastogenic agent while at the same time is the only soluble moiety known to be c-src inductive suggests that this cytokine may mediate implant particle-induced osteoclastogenesis. Consistent with this hypothesis, prosthesis-derived wear particles, recovered at revision arthroplasty, dose-dependently prompt TNF secretion by BMMs. Similarly, particulate polymemthylmethacrylate, the major component of orthopedic implant cement, induces BMM expression of TNF mRNA and protein in a time- and dose-dependent manner. Furthermore, failure of BMMs derived from mice deleted of both the p55 and p75 TNF receptors to express c-src in response to polymemthyl-methacrylate indicates TNF is an essential mediator of particle induction of this osteoclast specific protein. To test the hypothesis that TNF mediates implant osteolysis, we established an in vivo murine model of this condition that histologically mirrors that of man. Verifying that TNF is essential to development of particle osteolysis, mice failing to express both the p55 and p75 TNF receptors are protected from the profound bone resorption attending polymemthyl-methacrylate particle implantation on calvariae of wild-type animals. Finally, the protective effect of deletion of both TNF receptors is recapitulated in mice lacking only the p55 receptor. Thus, targeting TNF and/or its p55 receptor may arrest wear particle osteolysis.

Activation of NF-KB signalling and TNFα-expression in THP-1 macrophages by TiAlV- and polyethylene-wear particles

“…Thus, there is evidence that LPS is a much stronger stimulator for activation of TNFa and NF-KB in macrophages in comparison to wear particles. The time courses of transactivation of TNFa promoter and secreted TNFa in this study are consistent to findings by Merkel et al [35]. They revealed that TNFa mRNA substantially escalates within 3 h of particle exposure after which it progressively declines.…”

“…Our data support recent findings that the NF-KB signalling pathway may be involved in wear particleinduced periprosthetic osteolysis [16,18,35,41,45]. Our study extends these results and shows for the first time that not only TiAlV-, mixed-, or PMMA-particles [35,40], but also polyethylene-particles induce an activation of NF-KB signalling and the TNFa-promoter.…”

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

“…For instance, osteolysis is correlated with higher wear rates, 4,5 abundant wear particles are associated with periprosthetic tissues recovered during revision surgery, [6][7][8] and implantation of wear debris can trigger osteolysis in animal models. [9][10][11][12][13][14] A common theme which has emerged is that a critical initiating event in wear debris action is activation of pro-inflammatory cytokine signaling within periprosthetic macrophages, which in turn leads to an imbalance in the levels of the key osteoclastogenesis regulators RANKL and OPG. [15][16][17][18] However, the precise molecular and cellular pathogenesis whereby prosthetic wear debris leads to osteolytic bone loss remains unclear.…”

NF‐kB signaling blockade abolishes implant particle‐induced osteoclastogenesis

“…lysis [11,12,15,27,30,35]. The osteoclastogenic action of these cytokines is thought to be primarily mediated through induction of the nuclear transcription factor NF-kB which is known to be essential for osteoclastogenesis [20].…”