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Association of increased expression of macrophage elastase (matrix metalloproteinase 12) with rheumatoid arthritis
Mozhen Liu1, Huijun Sun, Xiaofei Wang
1Dalian Medical University, Dalian, China.
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.
Insights
Matrix metalloproteinase-12 (MMP-12) is significantly elevated in rheumatoid arthritis (RA) synovial tissue and fluid. Macrophage-derived MMP-12 may drive RA pathogenesis, suggesting MMP-12 inhibition as a potential treatment.
Area of Science:
- Rheumatology
- Immunology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) enzymatic activity is implicated in rheumatoid arthritis (RA) progression.
- Human macrophage elastase (MMP-12) role in RA pathogenesis requires further investigation.
Purpose of the Study:
- To investigate MMP-12 expression and localization in RA synovial tissue.
- To compare MMP-12 levels in RA versus osteoarthritis (OA) synovial tissue and fluid.
Main Methods:
- Synovial tissue and fluid samples from RA and OA patients.
- Immunohistochemistry, Northern blotting, Western blotting, and zymography were employed.
- MMP-12 quantification in tissue and synovial fluid.
Main Results:
- RA synovial tissue showed significantly higher MMP-12 mRNA and protein levels than OA.
- Elevated active MMP-12 forms with caseinolytic activity were found in RA tissue and fluid.
- MMP-12 was primarily expressed by synovial lining cells, including inflammatory macrophages.
Conclusions:
- Macrophage-derived MMP-12 likely contributes to RA's destructive processes.
- Inhibiting MMP-12 presents a potential therapeutic strategy for RA treatment.
