Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in rheumatoid synovium

In vitro, membrane-type matrix metalloproteinases (MT-MMP) are known to act ivate the zymogen of MMP-2 (proMMP-2, progelatinase A), which is one of the key MMP in joint destruction in rheumatoid arthritis. In the present study , we examined the production and activation of proMMP-2, and the expression of MT1-MMP, MT2-MMP, and MT3-MMP, their correlation with proMMP-2 activati on, and their localization in rheumatoid synovial tissue. Using sandwich en zyme immunoassay and gelatin zymography techniques, proMMP-2 production lev els and activation ratios were found to be significantly higher in rheumato id synovium compared with normal synovium (p < 0.01). Quantitative RT-PCR a nalyses demonstrated that MT1-MMP and MT3-MMP were expressed in all rheumat oid synovial tissue (30 of 30 cases), but that the mean expression level of MT1-MMP was approximately Ii-fold higher than MT3-MMP. Significant correla tion was found between the mRNA expression level of MT1-MMP and the activat ion ratio of proMMP-2 (p < 0.01). In situ hybridization indicated that the hyperplastic lining cells of rheumatoid synovium expressed MT1-MMP. Immunoh istochemistry demonstrated that MT1-MMP was co-localized with MMP-2 and wit h a tissue inhibitor of metalloproteinase-e, and was mainly located in the rheumatoid synovial lining cells. In situ zymography of rheumatoid synovium showed gelatinolytic activity, predominantly in the lining cell layer. Thi s activity was blocked when incubated with BB94, a specific MMP inhibitor. These results demonstrate that MT1-MMP plays an important role in the activ ation of proMMP-2 in the rheumatoid synovial lining cell layer, and suggest that its activity may be involved in the cartilage destruction of rheumato id arthritis.