Inhibitory effect of CD147/HAb18 monoclonal antibody on cartilage erosion and synovitis in the SCID mouse model for rheumatoid arthritis.

OBJECTIVE: To explore the therapeutic potential of CD147/HAb18 mAb in the treatment of RA in severe combined immunodeficiency (SCID) mice engrafted with human cartilage and rheumatoid synovium tissue (SCID-HuRAg). METHODS: SCID-HuRAg mice were treated separately with CD147/HAb18 mAb, anti-TNF-alpha mAb or a combination of both. The mice in control group were treated with anti-Japanese encephalitis virus mAb. The volume of engrafts was measured and the number of inflammatory cells and cartilage erosion score were examined. Expression of MMP-2, -3 and -9 was determined by immunohistochemistry. Human inflammatory cytokine levels in mouse sera were assessed using cytometric bead array kit. RESULTS: The volume of engrafts decreased significantly in SCID-HuRAg mice treated separately with anti-CD147 mAb or anti-TNF-alpha mAb, and in the mice treated with anti-CD147 mAb plus anti-TNF-alpha mAb (P < 0.05). Significant reduction was observed in cartilage erosion score in anti-CD147 treatment group and combined treatment group (P < 0.05). Immunohistochemical analysis showed that expression of MMP-2, -3 and -9 was lower in the anti-CD147 treatment group and combined treatment group than in the control mAb group (P < 0.05). Moreover, the level of TNF-alpha, IL-6 and -8 in CD147 mAb group showed a significant decrease compared with that of the control mAb group (P < 0.05). CONCLUSIONS: CD147/HAb18 mAb can reduce cartilage erosion and synovitis by inhibition of the MMPs and reduction of inflammatory cytokines in SCID-HuRAg mice, which suggests that CD147/HAb18 mAb is a promising treatment option for RA patients.

CD147 overexpression on synoviocytes in rheumatoid arthritis enhances matrix metalloproteinase production and invasiveness of synoviocytes.

Macrophage-like synoviocytes and fibroblast-like synoviocytes (FLS) are known as the most active cells of rheumatoid arthritis (RA) and are close to the articular cartilage in a position enabling them to invade the cartilage. Macrophage-like synoviocytes and FLS expression of matrix metalloproteinases (MMPs) and their interaction has aroused great interest. The present article studied the expression of CD147, also called extracellular matrix metalloproteinase inducer, on monocytes/macrophages and FLS from RA patients and its potential role in enhancing MMPs and the invasiveness of synoviocytes. Expression of CD147 on FLS derived from RA patients and from osteoarthritis patients, and expression of CD147 on monocytes/macrophages from rheumatic synovial fluid and healthy peripheral blood were analyzed by flow cytometry. The levels of CD147, MMP-2 and MMP-9 mRNA in FLS were detected by RT-PCR. The role of CD147 in MMP production and the cells' invasiveness in vitro were studied by the co-culture of FLS with the human THP-1 cell line or monocytes/macrophages, by gel zymography and by invasion assay. The results showed that the expression of CD147 was higher on RA FLS than on osteoarthritis FLS and was higher on monocytes/macrophages from rheumatic synovial fluid than on monocytes/macrophages from healthy peripheral blood. RT-PCR showed that the expressions of CD147, MMP-2 and MMP-9 mRNA was higher in RA FLS than in osteoarthritis FLS. A significantly elevated secretion and activation of MMP-2 and MMP-9 were observed in RA FLS co-cultured with differentiated THP-1 cells or RA synovial monocytes/macrophages, compared with those co-cultured with undifferentiated THP-1 cells or healthy control peripheral blood monocytes. Invasion assays showed an increased number of invading cells in the co-cultured RA FLS with differentiated THP-1 cells or RA synovial monocytes/macrophages. CD147 antagonistic peptide inhibited the MMP production and the invasive potential. Our studies demonstrated that the CD147 overexpression on monocytes/macrophages and FLS in RA patients may be responsible for the enhanced MMP secretion and activation and for the invasiveness of synoviocytes. These findings suggest that CD147 may be one of the important factors in progressive joint destruction of RA and that CD147 may be a potential therapeutic target in RA treatment.