Effect of cobalt and chromium ions on MMP-1, TIMP-1, and TNF- α 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 Co 2+ and Cr 3+ 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- α, 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 24 h with Co 2+ and Cr 3+ ions. The level of mRNAs was determined by reverse transcription-polymerase chain reaction (RT–PCR). Results show that both Co 2+ and Cr 3+ ions induce the expression of MMP-1, TIMP-1, and TNF- α 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- α expression. In contrast, herbimycin A completely blocks MMP-1 and TNF- α while partially inhibiting TIMP-1. However, Co 2+ and Cr 3+ 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 Co 2+ and Cr 3+ 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- α by Co 2+ and Cr 3+ ions is regulated by tyrosine kinases.