Aseptic Loosening Of Total Hip Replacement: Macrophage Expression Of Inducible Nitric Oxide Synthase And Cyclo-oxygenase-2, Together With Peroxynitrite Formation, As A Possible Mechanism For Early Prosthesis Failure

Abstract

Aseptic loosening is a major cause of failure of total hip arthroplasty. The adverse tissue response to prosthetic wear particles, with activation of cytokine and prostanoid production, contributes to bone loss around the implants. We have investigated the possibility that inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) are expressed in macrophages in the pseudomembrane at the bone-implant interface, thereby contributing to the periprosthetic bone resorption.We also assessed whether peroxynitrite, a nitric oxide (NO)-derived oxidant associated with cellular injury, is generated in the membrane. Enzymatic activity of iNOS was measured using the arginine-citrulline assay technique and prostaglandin E 2 (PGE 2 ), as an indicator of COX-2 activity, was measured using an enzyme immunoassay.Cellular immunoreactivity for iNOS, nitrotyrosine (a marker of peroxynitrite-induced cellular injury) and COX-2 was assessed by quantitative peroxidase immunocytochemistry while immunofluorescence methods were used for subsequent co-localisation studies with CD68 + macrophages.

Metallic but not ceramic wear particles increase prostaglandin E2 release and interleukin-1β gene expression in human blood monocytes in vitro

“…An overproduction of PGE 2 is thought to play a crucial role in the pathogenesis of aseptic loosening on membranes around the implant (22). The effect of metals on PGE 2 production is also consistent with the findings of Horowitz and colleagues, who showed an increased PGE 2 release induced by cobalt in macrophages (23).…”

Cytokine levels in synovial fluid from hips with well-functioning or loose prostheses

“…2,3 Early instability of the implant results in the formation of a fibrous membrane 4,5 containing macrophages which can induce bone resorption in a complex interaction with osteoblasts and osteoclasts. [6][7][8][9] Instability and particles seem to have a similar effect on the osteolytic process. 4,5,8 Particle disease is, however, the more accepted reason for the formation of granulomata, based on the finding of cytokine-producing macrophages loaded with particles in the periprosthetic tissue.…”

Nitric Oxide Activates Signaling by c-Raf, MEK, p-JNK, p38 MAPK and p53 in Human Mesenchymal Stromal Cells inhibits their Osteogenic Differentiation by Blocking Expression of Runx2

“…Oxidative stress plays an important role in aseptic loosening of orthopaedic endoprostheses [67,68] and high-output production of NO by CD68 + cells in the interface membrane was recorded [69,70]. We provide evidence that the elevated production of NO blocks the osteogenic differentiation of MSC by reducing the expression of Runx2 [54,71].…”