Expression of inflammatory cytokines, RANKL and OPG induced by titanium, cobalt-chromium and polyethylene particles
Introduction
Total hip arthroplasty (THA) is one of the most widely performed orthopaedic operations in recent years [1], [2]. With increases in the number of this procedure, periprosthetic osteolysis and aseptic loosening have become major foci of attention, because both phenomena promote instability of the prosthesis [3], [4]. In soft-tissue membranes harvested around loose prostheses, a foreign-body reaction due to implant-derived wear debris, polyethylene, metal and polymethylmethacrylate (PMMA) particles, has been observed [3], [5], [6]. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and prostaglandin E2 in the tissue surrounding failed implants have been implicated as factors in bone resorption [7], [8], [9], [10]. Several studies reported that wear particles stimulate macrophages to release inflammatory cytokines in vitro [11], [12], [13]. Particle-induced osteolysis was also shown in in vivo experiments, and was associated with the expression of inflammatory cytokines [14], [15], [16].
A receptor activator of nuclear factor-κB ligand (RANKL) is a member of the TNF superfamily that appears to play an important role in both immune responses and bone morphogenesis [17], [18], [19]. RANKL directly stimulates the differentiation and activation of osteoclasts through the membrane-bound TNF receptor superfamily member named RANK. Biological activity of RANKL is regulated by a soluble decoy receptor called osteoprotegerin (OPG) [20], [21]. OPG is a novel member of the TNF receptor superfamily and exists only in a soluble form unlike most other members of the TNF receptor family. The ratio in the expression of RANKL and OPG is critical to the outcome of bone resorption [22]. It was reported that exposure of PMMA particles to cultured bone marrow cells stimulates RANKL secretion [23]. Prosthetic metal particles have been shown to induce RANKL mRNA expression in human monocytes [24]. Recently, Kim et al. demonstrated decreased levels of OPG in failed THA [25]. These observations suggested that the balance of RANKL and OPG might be important in the differentiation of osteoclasts and the development of osteolysis. However, to our knowledge, no report has shown the induction of RANKL and OPG expression in in vivo experiments. In this study, we assessed the expression of inflammatory cytokines, RANKL and OPG induced by particles of Ti6Al4V, CoCr and high-density polyethylene (HDP) using a murine calvarial osteolysis model. Here, we show two types of osteoclastogenesis and osteolysis as related to the ratio of the expression of RANKL and OPG.
Section snippets
Preparation of particles
Particles of Ti6Al4V and CoCr were obtained from Zimmer (Warsaw, IN) and those of medical grade HDP from Sumitomo Fine Chemical Co. (Tokyo, Japan). These particles were suspended in distilled water and filtered using a microfiltration system (All Glass Filter System, Millipore, Ashby, MA) to obtain particles less than 5 μm in diameter followed by freeze-drying. Scanning electron microscopy (S-800S, HITACHI, Tokyo, Japan) was used to determine the size of the particles. The mean size and standard
Histological analysis
A faint inflammatory reaction was observed in the control tissues, but trabecular bone in the murine skull was well conserved (Fig. 2A). The tissues exposed to Ti6Al4V, CoCr or HDP particles for 7 days showed a marked inflammatory reaction with highly vascularized granulation containing macrophages and multi-nucleated giant cells (Figs. 2C, E and G). These granulation tissues were accompanied by disruption of the normal bony structure.
Osteolysis was quantitatively evaluated according to the
Discussion
In this study, the murine calvariae implanted with Ti6Al4V, CoCr or HDP particles showed significantly more extensive osteolysis that paralleled an increased number of osteoclasts. Increased levels of TNF-α and IL-1β were also identified after implantation of Ti6Al4V, CoCr or HDP. Previously the authors showed that Ti6Al4V, HDP, Al2O3 and ZrO2 particles induce IL-1β and IL-6 in a murine calvarial model [16]. These observations are consistent with reports that showed the expression of
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