Abstract
ABSTRACTMetal‐on‐metal (MOM) hip resurfacing has recently been a popular prosthesis choice for the treatment of symptomatic arthritis, but results in the release of cobalt and chromium ions into the circulation that can be associated with adverse clinical effects. The mechanism underlying these effects remains unclear. While chromosomal aneuploidy and translocations are associated with this exposure, the presence of subtle structural epigenetic modifications in patients with MOM joint replacements remains unexplored. Consequently, we analyzed whole blood DNA methylation in 34 OA patients with MOM hip resurfacing (MOM HR) compared to 34 OA patients with non‐MOM total hip replacements (non‐MOM THR), using the genome‐wide Illumina HumanMethylation 450k BeadChip. No probes showed differential methylation significant at 5% false‐discovery rate (FDR). We also tested association of probe methylation levels with blood chromium and cobalt levels directly; there were no significant associations at 5% FDR. Finally, we used the “epigenetic clock” to compare estimated to actual age at sample for all individuals. We found no significant difference between MOM HR and non‐MOM THR, and no correlation of age acceleration with blood metal levels. Our results suggest the absence of large methylation differences systemically following metal exposure, however, larger sample sizes will be required to identify potential small effects. Any DNA methylation changes that may occur in the local periprosthetic tissues remain to be elucidated. © 2017 The Authors. Orthopaedic Research Society. Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:2323–2328, 2017.
Highlights
Metal-on-metal (MOM) hip replacement and resurfacing have been, until recently, popular treatments of choice for patients with painful arthritis[1], with over 1.5 million devices inserted worldwide2; 3
Estimation of cell-type composition Since methylation levels were assessed in whole blood and could be influenced by cell type heterogeneity, we estimated the cell type composition of all samples[35].There were no significant differences in estimated proportions of CD8+ T-cells, CD4+ T-cells, B cells, natural killer (NK) cells, monocytes, and granulocytes between MOM hip resurfacing (MOM HR) and non-MOM THR samples (Wilcoxon test p-value >0.17 for difference in each of the cell types; Figure 1)
Differentially-methylated probes (DMPs) The probes were tested for differential methylation between MOM HR and non-MOM THR samples, using gender, age at sample, time since surgery, smoking, metal exposure not due to MOM HR, estimated cell type proportions, and the first principal component as covariates
Summary
Metal-on-metal (MOM) hip replacement and resurfacing have been, until recently, popular treatments of choice for patients with painful arthritis[1], with over 1.5 million devices inserted worldwide2; 3. Wear and corrosion occur at the bearing surfaces of MOM prostheses and at modular junctions of all hip prostheses4; 5. This causes the release of metallic wear debris into the local tissues and peripheral circulation, resulting in a systemic elevation of cobalt and chromium concentrations6; 7. The mechanism by which metal debris exerts these effects is still unclear, some investigators have studied changes in gene expression of candidate genes in cell and animal models[16,17,18]. Several studies have reported metal-induced changes in DNA methylation, alteration in gene expression and cell physiology in the setting of cancer[19,20,21]. The effects of chronic metal exposure on the patient epigenome and cell function in the setting of joint replacement remain unexplored
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