title: Effect of cobalt and chromium ions on MMP-1, TIMP-1, and TNF-alpha gene expression in human U937 macrophages: a role for tyrosine kinases.
abstract: Previous reports have suggested that the imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) activity may contribute to prosthetic loosening. However, the mechanisms controlling these enzymes in the periprosthetic environment is unknown. We examined the effect of Co2+ and Cr3+ ions on the expression of genes encoding MMP-1, one of the principal proteinases capable of degrading native fibrillar collagens in the extracellular matrix (ECM), its inhibitor TIMP-1, and TNF-alpha, a cytokine that plays a central role in the induction of implant osteolysis. Human U937 macrophages were incubated in suspension or on phosphorylcholine (PC)-polymer coated surfaces for 24h with Co2+ and Cr3+ ions. The level of mRNAs was determined by reverse transcription-polymerase chain reaction (RT-PCR). Results show that both Co2+ and Cr3+ ions induce the expression of MMP-1, TIMP-1, and TNF-alpha mRNA in a dose-dependent manner in cell suspensions. Tyrosine kinase inhibitors have different effects on these stimulatory effects. Indeed, genistein has only partial inhibitory effect on MMP-1 and TIMP-1, with even less effect on TNF-alpha expression. In contrast, herbimycin A completely blocks MMP-1 and TNF-alpha while partially inhibiting TIMP-1. However, Co2+ and Cr3+ ions had no effect on the expression of MMP-1 and TIMP-1 in macrophages cultured on the PC-polymer, suggesting that the attachment of U937 macrophages to the PC-polymer surfaces may modify their gene expression. In fact, MMP-1 and TIMP-1 seems to be constitutively up-regulated in this condition. However, the effect of Co2+ and Cr3+ ions on macrophages cultured on PC-polymer coated surfaces is similar to what was observed in suspension. Together, these findings indicate that activation of MMP-1, TIMP-1, and TNF-alpha by Co2+ and Cr3+ ions is regulated by tyrosine kinases.
authors.affiliation: Division of Orthopaedic Surgery, McGill University, Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, 3755 Chemin de la Côte Ste-Catherine, Montréal, Québec, Canada H3T 1E2.
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.forename: Alain
authors.initials: A
authors.lastname: Petit
authors.forename: John
authors.initials: J
authors.lastname: Antoniou
authors.forename: David J
authors.initials: DJ
authors.lastname: Zukor
authors.forename: Olga L
authors.initials: OL
authors.lastname: Huk
authors.forename: Roger C W
authors.initials: RC
authors.lastname: Liu
authors.forename: Françoise M
authors.initials: FM
authors.lastname: Winnik
authors.forename: Fackson
authors.initials: F
authors.lastname: Mwale
mesh_terms: D002460:Cell Line; D002857:Chromium / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007477:Ions; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D007477:Ions; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D002857:Chromium; D003035:Cobalt; D020781:Matrix Metalloproteinase 1