EFFECT OF COBALT AND CHROMIUM IONS ON THE EXPRESSION OF MATRIX METALLOPROTEINASE-1 (MMP-1) AND TISSUE INHIBITOR OF METALLOPROTEINASE-1 (TIMP-1) IN HUMAN U937 MACROPHAGES IN VITRO.

Abstract

The in situ increased production of matrix metalloproteinases (MMPs) has been associated with the development of periprosthetic osteolysis. The aim of the study was to compare the effect of Co²⁺ and Cr³⁺ ions on macrophages matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of MMP (TIMP-1) expression. Using reverse transcription-polymerase chain reaction (RT-PCR), we showed that both Co²⁺ and Cr³⁺ ions induce the expression of MMP-1 and TIMP-1 in a dose-dependent manner. Since MMP-1 and TIMP-1 participate in the extracellular matrix degradation and tissue remodeling, our results suggest that the modulation of MMP-1 and TIMP-1 may contribute to the development of periprosthetic osteolysis.

The in situ increased production of matrix metalloproteinases (MMPs) has been associated with the development of periprosthetic osteolysis. Aseptic loosening due to periprosthetic osteolysis is the major cause of total hip arthroplasty failure. Because of their potential for improved wear performance, there has been a revived interest in metal-metal bearings, made of cobalt-chromium-molybdenum alloys. However, metal particle and ion toxicity remains a major cause for concern.

The aim of the study was to determine the effects of Co²⁺ and Cr³⁺ ions on the expression of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1), two proteins participating in the extracellular matrix degradation and tissue remodeling.

Human U937 macrophages were incubated with Co²⁺ and Cr³⁺ ions. The expression of MMP-1 and TIMP-1 mRNAs was measured by reverse transcription-polymerase chain reaction (RT-PCR) and calculated as the ratio of the house keeping gene GAPDH expression.

Results show that both Co²⁺ and Cr³⁺ ions induced in a dose-dependent manner the expression of PCR products (mRNAs) of MMP-1 (135 bp) and TIMP-1 (328 bp). Co²⁺ ions were more effective in inducing MMP-1 and TIMP-1 expression than Cr³⁺ ions. The induction of MMP-1 and TIMP-1 paralleled the induction of TNF-α mRNA expression.

Our results demonstrate that the expression of MMP-1 and TIMP-1 were up regulated by incubating macrophages with Co²⁺ and Cr³⁺ ions, suggesting that metal ions contribute to tissue damage in the periprosthetic environment and that variations in MMP-1 and TIMP-1 expression may contribute to periprosthetic osteolysis.