Expression of Concern: Different apoptosis modalities in periprosthetic membranes

Abstract

This study reports on an investigation into apoptotic and proliferation signals in leukocyte and membrane fibroblasts in periprosthetic membranes collected during revision surgery for loosened total hip joint arthroplasty. Cementless and cemented prosthesis were studied under both aseptic and septic conditions. Fluorescence colocalization immunohistochemistry and colorimetric immunohistochemistry were used to investigate cell death signals. In aseptic cementless prosthesis macrophages and membrane fibroblasts show high bax signal, implying the occurrence of toxic/oxidative cell death caused by the debris of titanium alloy metal implant. Instead in aseptic cemented prosthesis only a moderate number of apoptotic leukocytes were observed, whilst the fibroblasts were affected by a diffuse apoptotic-like cell death, the Co-Cr ions debris released from cemented stem, may be at basis of apoptotic cell death induction. Furthermore cement debris is recognized to induce macrophages to produce cytokine, that may be responsible for the cell death observed and implant failure. The septic environment seems to protect leukocytes cell death. Septic cementless prosthesis showed only a few apoptotic leukocytes, instead fibroblasts remain affected by cell death signals. Similarly in septic cemented prosthesis, scanty apoptotic leukocytes were detected, whereas membrane fibroblasts showed an increase in proliferation index (Ki-67) along with caspase-3 activation. These findings indicate some kind of caspase-3 involvement in tissue proliferation, rather than in cell death pathway. Apoptotic periprosthetic sites have been interpreted as signs of inflammation resolution and normal tissue turnover. Nevertheless apoptosis may also be a sign of cell renewal associated to tissue proliferation.

Contributions of human tissue analysis to understanding the mechanisms of loosening and osteolysis in total hip replacement

“…Some authors followed an immunofluorescence staining protocol [38,40,50,61,68], while others preferred antigens labeled by enzymes [38,48,50,61,68,69]. …”

“…In favor of this hypothesis, several studies have shown bacterial by-products, including bacterial DNA, in periprosthetic tissue homogenates [82]. Additionally, septic membranes have a significantly higher number of CD45+ leukocytes, while aseptic membranes show a preponderance of CD68+ macrophages and histiocytes [57,69]. However, tissues with low-grade infection can appear like tissues retrieved from patients with aseptic loosening.…”

“…Polyethylene particles smaller than 5–7 µm can be observed within macrophages [42,47], while larger particles induce a foreign body giant cell reaction – with the amount of particles correlating with the number of foreign body giant cells [19,32]. Generally, tissues with increased numbers of wear particles have the appearance of foreign body granuloma [19,66,69,88,89]. …”

“…Apoptosis can contribute to the resolution of inflammation, the normalization of tissue turnover and the processes of cell renewal accompanying tissue proliferation [69,84]. In contrast, insufficient apoptosis could contribute to the growth of granulomatous tissue and prolonged production of proteolytic enzymes.…”

“…In contrast, insufficient apoptosis could contribute to the growth of granulomatous tissue and prolonged production of proteolytic enzymes. In fact, a number of studies have shown apoptotic activity of various cells in peri-implant tissues around loosened THAs [59,62,63,66,69]. The low immunopositivity of the apoptotic markers in fact correlated with the degree of osteolysis, and with the proliferation of macro-phages and fibroblasts [63].…”