Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. The purpose of the current study was to identify various apoptosis-related pathways in the cellular response to wear debris. Fas receptor, BAK and caspase-3 cleaved were evaluated immunohistochemically in capsules and interface membranes from patients with aseptic hip implant loosening. Moreover, we investigated local cellular proliferation, documented by the presence of Ki-67, to evaluate the proportion of apoptosis in relation to the proliferation in the different cells. We detected a strong expression of caspase-3 cleaved, Fas and BAK in macrophages, giant cells and T-lymphocytes. The fibroblasts showed caspase-3 cleaved and BAK, but no Fas staining. Demonstrated by Ki-67 staining, we found increased proliferation of macrophages and fibroblasts. Statistical analysis showed a significant positive correlation (p<0.001) between the above mentioned results and the presence of wear debris. The intensity of apoptosis and proliferation differed, depending on the extent of osteolysis. Overall, four different patterns of immunoreactivity were identified. We think, however, that in particle-induced osteolysis apoptosis is pathologically increased - a phenomenon also seen in other diseases. In these instances, the number and degree of apoptotic reactions are so great that the resulting cell remains cannot be completely removed. This leads to an increased excretion of fibrogenic mediators that could be responsible for increased proliferation of fibroblasts in spite of the increased apoptosis. Moreover, it leads to an increased excretion of cytokines which could be responsible for the activation of osteoclasts.
"Apoptotic markers FAS  BAK   BAX   TUNEL    cytochrome c  iNOS   Nitrotyrosine   p53  Inhibitors of apoptosis Survivin  B-cell CLL/lymphoma 2   XIAP  and eventually in implant loosening is currently unclear. Metal ions, or haptens such as acrylates, primarily form covalent bonds between the electrophilic components of the hapten and the amino acid nucleophilic side chains of the target proteins. "
[Show abstract][Hide abstract] ABSTRACT: Aseptic loosening and osteolysis are the most frequent late complications of total hip arthroplasty (THA) leading to revision of the prosthesis. This review aims to demonstrate how histopathological studies contribute to our understanding of the mechanisms of aseptic loosening/ osteolysis development. Only studies analysing periprosthetic tissues retrieved from failed implants in humans were included. Data from 101 studies (5532 patients with failure of THA implants) published in English or German between 1974 - 2013 were included. “Control” samples were reported in 45 (45%) of the 101 studies. The most frequently examined tissues were the bone-implant interface membrane and pseudosynovial tissues. Histopathological studies contribute importantly to determination of key cell populations underlying the biologic mechanisms of aseptic loosening and osteolysis. The studies demonstrated the key molecules of the host response at the protein level (chemokines, cytokines, nitric oxide metabolites, metalloproteinases). However, these studies also have important limitations. Tissues harvested at revision surgery reflect specifically end-stage failure and may not adequately reveal the evolution of pathophysiological events that lead to prosthetic loosening and osteolysis. One possible solution is to examine tissues harvested from stable total hip arthroplasties that have been revised at various time periods due to dislocation or periprosthetic fracture in multicentre studies.
"There is a growing need for more targeted approaches of diagnosis and early intervention of unwanted debris-induced inflammation. New understanding of how sterile nonpathogen implant debris causes immune activation and other local reaction continue to be discovered, such as the inflammasome “danger signalling” pathway , and the induction of hypoxia and apoptosis related reactivity [52, 55, 56, 79]. Consequently new therapies (such as anti-TNF-infliximab, anti-IL-1β, IL-1β-receptor-antagonist anakinra, etc.) are under current investigation as targeting measurement and pharmacologic interventions. "
[Show abstract][Hide abstract] ABSTRACT: All of the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after 15-25 years of use, due to slow progressive subtle inflammation at the bone implant interface. This inflammatory disease state is caused by implant debris acting, primarily, on innate immune cells, that is, macrophages. This slow progressive pathological bone loss or "aseptic loosening" is a potentially life-threatening condition due to the serious complications in older people (>75 yrs) of total joint replacement revision surgery. In some people implant debris (particles and ions from metals) can influence the adaptive immune system as well, giving rise to the concept of metal sensitivity. However, a consensus of studies agrees that the dominant form of this response is due to innate reactivity by macrophages to implant debris where both danger (DAMP) and pathogen (PAMP) signalling elicit cytokine-based inflammatory responses. This paper discusses implant debris induced release of the cytokines and chemokines due to activation of the innate (and the adaptive) immune system and the subsequent formation of osteolysis. Different mechanisms of implant-debris reactivity related to the innate immune system are detailed, for example, danger signalling (e.g., IL-1β, IL-18, IL-33, etc.), toll-like receptor activation (e.g., IL-6, TNF-α, etc.), apoptosis (e.g., caspases 3-9), bone catabolism (e.g., TRAP5b), and hypoxia responses (Hif1-α). Cytokine-based clinical and basic science studies are in progress to provide diagnosis and therapeutic intervention strategies.
Mediators of Inflammation 05/2014; 2014:185150. DOI:10.1155/2014/185150 · 3.24 Impact Factor
"This process results in implant instability requiring expensive revision surgery. We have recently published two articles about the influence of apoptosis (Landgraeber, Toetsch et al. 2006; Landgraeber, von Knoch et al. 2008) and neuropeptides (i.e. alpha - Calcitonin-Gene Related Peptide (CGRP) (Wedemeyer, Neuerburg et al. 2007) in aseptic loosening. "
[Show abstract][Hide abstract] ABSTRACT: The search for influencing factors and new pathways in aseptic loosening of arthroplasties is a major focus of recent studies. Analyses of polymorphisms of genes revealed a correlation between a specific allele variant and aseptic loosening. The BCL2 gene encoding Bcl-2 with its BCL2 -938C>A polymorphism is a crucial factor of cell cycle control and cell survival. The CALCA -1786T>C polymorphism belongs to the CALCA gene encoding alpha-Calcitonin Gene Related Peptide (CGRP) and Calcitonin. Both proteins are important in bone metabolism and capable to influence the process of aseptic loosening. To date, no studies are reported for aseptic loosening with these two single nucleotide polymorphisms (SNPs). In a retrospective study we determined the distribution of the BCL2-938C>A and the CALCA-1786T>C polymorphisms in 87 subjects with aseptic loosened hip arthroplasties using RFLP and pyrosequencing analysis. Genotype distribution with prognosis of the hip arthroplasty showed neither an association with clinical characteristics of the patients nor the implantation technique. We were unable to detect any influence of these polymorphisms on time to aseptic loosening. motion.
European journal of medical research 06/2009; 14(6):250-5. DOI:10.1186/2047-783X-14-6-250 · 1.50 Impact Factor
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