Association of increased expression of macrophage elastase (matrix metalloproteinase 12) with rheumatoid arthritis

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Abstract
Objective Increased enzymatic activity of matrix metalloproteinases (MMPs) may promote the progression of rheumatoid arthritis (RA). We undertook this study to investigate the expression and localization of human macrophage elastase (MMP‐12) in synovial tissue from RA patients and to compare MMP‐12 levels in the synovial tissue and synovial fluid of RA patients with the corresponding levels in patients with osteoarthritis (OA). Methods We obtained synovial tissues from 23 RA patients and 29 OA patients and analyzed MMP‐12 expression using immunohistochemistry, Western and Northern blotting analyses, and zymography. Furthermore, we quantified MMP‐12 levels in synovial fluid by Western blotting and zymography. Results Northern blotting analysis demonstrated that RA synovial tissue contained higher levels of MMP‐12 messenger RNA than did OA synovial tissue. Western blotting revealed that MMP‐12 proteins were consistently and markedly increased in RA synovial tissue compared with OA synovial tissue. A greater amount of immunoreactive proteins corresponding to catalytic forms of MMP‐12 was present in RA synovial tissue and synovial fluid, and the MMP‐12 proteins exhibited caseinolytic activity in vitro. Immunohistochemical staining showed that the major cells expressing MMP‐12 were synovial lining cells, many of which were inflammatory macrophages. Conclusion These results establish a possible mechanism by which macrophage‐derived MMP‐12 may play an important role in the destructive process in RA. Inhibition of MMP‐12 may be a potential modality for the treatment of RA.