title: Over-expression of p53/BAK in aseptic loosening after total hip replacement.
abstract: Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. The possible induction of apoptosis has not been addressed in great detail. Thus far, it has been shown that ceramic and polyethylene particles can induce apoptosis of macrophages in vitro. The purpose of this study was to test the hypothesis that wears debris generated from total hip arthroplasty could induce cellular damage and apoptosis in vivo. We therefore determined by immunohistochemical methods if increased expression of p53, an important transcription factor, and BAK and Bcl-2, two important regulators of apoptosis, can be found in interface membranes and capsules of hips with aseptically loose implants. Strongly positive immunohistochemical staining for p53 and BAK was found in peri-implant tissues from patients with aseptic hip implant loosening. Differentiation of various cell types showed that macrophages stained positive for p53 in all capsule and interface specimens. p53 was frequently detected in giant cells. Positive staining of BAK in macrophages and giant cells was seen in all specimens. Some positive reactions were observed in fibroblasts, only two of 19 cases stained for p53 and three cases for BAK within synovial cells. Positive macrophages and giant cells were localized around polyethylene particles. While T-lymphocytes showed a regular BAK-staining, the other leukocytes were negative. Statistical analyses showed significant positive correlations (p < 0.001) between the presence of polyethylene and metal debris and the expression of BAK and p53. Polyethylene particles were surrounded by more positive macrophages and giant cells than were metal particles, indicating that polyethylene debris may be a stronger inductor of cell cycle arrest and apoptosis than metal debris. In this study apoptosis of macrophages, giant cells and T-lymphocytes in capsules and interface membranes of patients with aseptic hip implant loosening has been demonstrated in vivo. It is possible that the apoptotic cascade could evolve as a novel therapeutic target to prevent particle-induced osteolysis.
authors.affiliation: Department of Orthopaedics, University of Duisburg-Essen, Pattbergstrasse 1-3, 45239 Essen, Germany. stlandy@arcor.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Landgraeber
authors.forename: Martin
authors.initials: M
authors.lastname: Toetsch
authors.forename: Christian
authors.initials: C
authors.lastname: Wedemeyer
authors.forename: Guido
authors.initials: G
authors.lastname: Saxler
authors.forename: Michael
authors.initials: M
authors.lastname: Tsokos
authors.forename: Fabian
authors.initials: F
authors.lastname: von Knoch
authors.forename: Markus
authors.initials: M
authors.lastname: Neuhäuser
authors.forename: Franz
authors.initials: F
authors.lastname: Löer
authors.forename: Marius
authors.initials: M
authors.lastname: von Knoch
mesh_terms: D000328:Adult; D000368:Aged; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects; D002478:Cells, Cultured; D005260:Female; D005549:Foreign-Body Reaction / Q000209:etiology / Q000378:metabolism*; D006621:Hip Joint / Q000378:metabolism* / Q000601:surgery; D006801:Humans; D007593:Joint Instability / Q000209:etiology / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016459:Prosthesis-Related Infections / Q000209:etiology / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
chemical_list: C494772:BAK1 protein, human; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein