Macrophage migration inhibitory factor up-regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis

Neutral matrix metalloproteinases (MMPs) are responsible for the pathologic al features of rheumatoid arthritis (RA) such as degradation of cartilage. We herein show the up-regulation of MMP-1 (interstitial collagenase) and MM P-3 (stromelysin) mRNAs of cultured synovial fibroblasts retrieved from rhe umatoid arthritis (RA) patients in response to macrophage migration inhibit ory factor (MIF). The elevation of MMP-1 and MMP-3 mRNA was dose-dependent and started at 6 h post-stimulation by MIF, reached the maximum level at 24 h, and was sustained at least up to 36 h. Interleukin (IL)-1 beta mRNA was also up-regulated by MIF. These events were preceded by up-regulation of c -jun and c-fos mRNA. Tissue inhibitor of metalloproteinase (TIMP)-1, a comm on inhibitor of these proteases, was slightly upregulated by MIF, Similarly , mRNA up-regulation of MMP-1 and MMP-3 was observed in the synovial fibrob lasts of patients with osteoarthritis. However, their expression levels wer e much lower than those of RA synovial fibroblasts. The mRNA up-regulation by MIF was inhibited by the tyrosine kinase inhibitors genestein and herbim ycin A, as well as the protein kinase C inhibitors staurosporine and H-7. O n the other hand, the inhibition was not seen after the addition of the cyc lic AMP dependent kinase inhibitor, H-8. The mRNA upregulation of MMPs was also inhibited by curcumin, an inhibitor of transcription factor AP-1, wher eas interleukin-1 receptor antagonist, an IL-1 receptor antagonist, failed to inhibit the mRNA up-regulation, Considering these results, it is suggest ed that 1) MTF plays an important role in the tissue destruction of rheumat oid joints via induction of the proteinases, and 2) MIF up-regulates MMP-1 and MMP-3 via tyrosine kinase-, protein kinase C-, and AP-1- dependent path ways, bypassing IL-1 beta signal transduction.