title: CoCr wear particles generated from CoCr alloy metal-on-metal hip replacements, and cobalt ions stimulate apoptosis and expression of general toxicology-related genes in monocyte-like U937 cells.
abstract: Cobalt-chromium (CoCr) particles in the nanometre size range and their concomitant release of Co and Cr ions into the patients' circulation are produced by wear at the articulating surfaces of metal-on-metal (MoM) implants. This process is associated with inflammation, bone loss and implant loosening and led to the withdrawal from the market of the DePuy ASR™ MoM hip replacements in 2010. Ions released from CoCr particles derived from a resurfacing implant in vitro and their subsequent cellular up-take were measured by ICP-MS. Moreover, the ability of such metal debris and Co ions to induce both apoptosis was evaluated with both FACS and immunoblotting. qRT-PCR was used to assess the effects on the expression of lymphotoxin alpha (LTA), BCL2-associated athanogene (BAG1), nitric oxide synthase 2 inducible (NOS2), FBJ murine osteosarcoma viral oncogene homolog (FOS), growth arrest and DNA-damage-inducible alpha (GADD45A). ICP-MS showed that the wear debris released significant (p<0.05) amounts of Co and Cr ions into the culture medium, and significant (p<0.05) cellular uptake of both ions. There was also an increase (p<0.05) in apoptosis after a 48h exposure to wear debris. Analysis of qRT-PCR results found significant up-regulation (p<0.05) particularly of NOS2 and BAG1 in Co pre-treated cells which were subsequently exposed to Co ions+debris. Metal debris was more effective as an inducer of apoptosis and gene expression when cells had been pre-treated with Co ions. This suggests that if a patient receives sequential bilateral CoCr implants, the second implant may be more likely to produce adverse effects than the first one.
authors.affiliation: Biomedical Engineering Department, University of Strathclyde, Wolfson Centre, Glasgow G4 0NW, UK. Electronic address: O.M.PosadaEstefan@leeds.ac.uk.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Posada
authors.affiliation: Pure and Applied Chemistry Department, University of Strathclyde, Thomas Graham Building, Glasgow G1 1XL, UK.
authors.forename: Denise
authors.initials: D
authors.lastname: Gilmour
authors.affiliation: Strathclyde Institute for Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. Electronic address: r.j.tate@strath.ac.uk.
authors.forename: Rothwelle J
authors.initials: RJ
authors.lastname: Tate
authors.affiliation: Biomedical Engineering Department, University of Strathclyde, Wolfson Centre, Glasgow G4 0NW, UK.
authors.forename: M Helen
authors.initials: MH
authors.lastname: Grant
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002857:Chromium / Q000378:metabolism* / Q000633:toxicity; D002858:Chromium Alloys / Q000378:metabolism / Q000633:toxicity; D003035:Cobalt / Q000378:metabolism* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D061825:Metal-on-Metal Joint Prostheses / Q000009:adverse effects*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D002858:Chromium Alloys; D002857:Chromium; D003035:Cobalt
keywords: Apoptosis; Co ions; CoCr wear debris; Metal-on-metal; Toxicology