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

Abstract

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 cocultured 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.

The Secretome Derived From Mesenchymal Stromal Cells Cultured in a Xeno-Free Medium Promotes Human Cartilage Recovery in vitro

“…Its role is controversial. Some studies have correlated this molecule to the increase of MMPs production and the progression of joint destruction in RA and OA (Tomita et al, 2002;Zhu et al, 2006). However, EMMPRIN has been demonstrated to inhibit TNF-induced apoptosis and the NF-kB-dependent proinflammatory cytokines secretion in synovial tissue during RA (Zhai et al, 2016).…”

Multiple myeloma cell-derived microvesicles are enriched in CD147 expression and enhance tumor cell proliferation

“…Finally, it is important to acknowledge that MM-derived MVs are highly likely to have biological effects on other cell types in the microenvironment. It is also probable that the CD147 molecule in MVs contributes to this activity as well given the known ability of CD147 to enhance angiogenesis and stimulate extracellular matrix degradation [28, 29]. Indeed, studies of this nature are currently underway.…”

“…CD147, also known as extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN), is a transmembrane glycoprotein ubiquitously expressed at a low level on the surface of many different cell types [26]. Increased CD147 expression is biologically relevant because of its ability to increase angiogenesis [27], tumor growth [28], and MMP production leading to extracellular matrix degradation [28, 29]. Based on these findings as well as the growing body of literature regarding the role of MVs in intercellular communication, the aim of the present study was to continue our research of CD147 by investigating its potential involvement in the disease as a constituent of MM cell released MVs.…”

Function of CD147 in Atherosclerosis and Atherothrombosis

“…CD147 may be a promising therapeutic target for treating atherosclerosis and atherothrombosis. CD147-blocking antibodies, antagonistic peptides [83], and siRNA have been used in animal models to reduce tissue inflammation. CD147 +/− mice and mAb anti-CD147-treated WT-mice are largely protected from myocardial I/R injury [56].…”