A novel bisphosphonate inhibits inflammatory bone resorption in a rat osteolysis model with continuous infusion of polyethylene particles

Abstract

This study examined the inhibitory effect of a new bisphosphonate (TRK-530) on wear debris-mediated bone resorption in a rat osteolysis model involving continuous infusion of high density polyethylene (HDPE) particles. TRK-530 (TRK) is a novel synthetic bispliosphonate that has been shown to decrease the level of tumor necrosis factor alpha (TNF-a) in the bone marrow of rats with adjuvant arthritis. Forty Wistar rats were randomized to two groups ( i i = 20 each). In each rat, 8 Kirsliner (K) wire was inserted into tlie femur and HDPE particles were continuously infused into the knee joint. Thereafter, the animals were subcutaneously injected with saline (control group) or I mg/kg of TRK (TRK group) every second day, and were sacrificed at 4 or 8 weeks after surgery. Radiographs obtained a t the time of sacrifice were evaluated for periprosthetic osteolysis. We also examined the thickness of the reactive membrane a s well as the number of osteoclast-like cells around tlie K-wire. In addition, we examined the expression of genes for bone-resorbing cytokines in the reactive membrane. Radiographic peri-implant osteolysis was more frequent in the control group coinpared with the TRK group at each time of assessinent 0, < 0.01). The interfacial membrane was significantly thinner in the TRK group coinpared with the control group ( p < 0.01) and the average number of osteoclast-like cells around tlie Kwire was significantly fewer in the TRK group (p < 0.01). I n addition, the expression of interleukin 1 -alpha messenger ribonucleic acid (IL-la niRNA) and TNF-a niRNA was suppressed in the T R K group at each time of assessnient. We conclude that the T R K can inhibit the formation of inflaniinatory peri-implant osteolysis induced by HDPE particles.

Inhibiting wear particles-induced osteolysis with doxycycline

“…So inhibiting osteoclastogenesis and inflammation is an important step in treating wear particles induced by osteolysis. Many efforts have been made to treat or prevent wear particle osteolysis [6,13,[21][22][23][24][25][26] . Until now, only etanercept, a TNFα receptor antagonist and bisphosphonate, has been applied in clinical situations after total joint arthroplasty [26][27][28] .…”

Periprosthetic osteolysis: genetics, mechanisms and potential therapeutic interventions

“…A novel synthetic bisphosphonate, TRK-530, has been shown to reduce bone resorption in rats with adjuvant arthritis by inhibiting the IL-1-like activity of resident peritoneal macrophages and by decreasing the bone marrow levels of cytokine-induced neutrophil chemoattractant-1 and TNF-α. Iwase and colleagues 46 randomly assigned 40 Wistar rats to 2 groups. In each rat, a Kwire was inserted into the femur and high-density PE particles were continuously infused into the knee joint.…”

Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis

“…Numerous in vivo and in vitro models have been developed to investigate the interactions among macrophages and other cells, wear debris, and osteolysis [1, 3, 8, 12, 16-20, 22, 29, 30, 33, 34, 42]. Instead of pumping particles into the knee and inserting a solid wire into the femoral medullary canal, we modified the rat model of Kim et al [18,22] by implanting a hollow titanium rod in the distal part of the femur and pumping particles into the femoral bone marrow cavity directly. In this modified mouse model, polyethylene particles were infused continuously into the femur through an osmotic pump to simulate the clinical scenario more closely [25,26,31,32].…”