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

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.

Overexpression of Human Matrix Metalloproteinase-12 Enhances the Development of Inflammatory Arthritis in Transgenic Rabbits

“…22 Although these results indicate that MMP-12 may be associated with RA, it is not clear whether MMP-12 directly participates in the pathogenesis of RA. In this study, we examined the hypothesis that increased MMP-12 potentially enhances the progress of inflammatory arthritis.…”

“…22 To examine the hypothesis that MMP-12 may act as an important mediator in the pathogenesis of RA, we used MMP-12 transgenic (Tg) rabbits that specifically overexpress human MMP-12 only in macrophages and investigated the effect of overexpressed MMP-12 on the development of experimentally induced inflammatory arthritis. To the best of our knowledge, the present study provides the first evidence showing that MMP-12 up-regulation affects the process of inflammatory arthritis.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Ample evidence has shown that in the synovial membrane of RA patients, the number of macrophages is correlated to the extent of joint destruction (Tak et al, 1997). Further, it has been demonstrated that synovial tissue and fluid obtained from patients with rheumatoid arthritis contained higher activity of MMP-12 (Liu et al, 2004).…”

Macrophage Metalloelastase Accelerates the Progression of Atherosclerosis in Transgenic Rabbits

“…MMP-12, also called macrophage metalloelastase, was first identified as a potent elastolytic metalloproteinase specifically secreted by macrophages, 14,15 and increased activity of MMP-12 from inflammatory macrophages is associated with several destructive diseases, including emphysema, 16,17 rheumatoid and inflammatory arthritis, 18,19 skin diseases, 20 and abdominal aortic aneurysms. 21 In addition to elastin, MMP-12 also is able to degrade a broad spectrum of ECM components such as collagen type IV, fibronectin, laminin, vitronectin, proteoglycans, and plasminogen.…”