Rheumatoid synovial endothelial cells secrete decreased levels of tissue inhibitor of MMP (TIMP1)

Abstract

Objectives-Angiogenesis (the formation of new blood vessels) is a major component of the inflammatory pannus in rheumatoid arthritis (RA). Matrix metalloproteinase (MMP) secretion by microvascular endothelial cells is an essential step in angiogenesis. The secretion of MMP1, MMP2, MMP9, and TIMP1 by human microvascular endothelial cells derived from RA synovium (RASE) to normal synovium (NSE) and neonatal foreskin (FSE) was compared. Methods-Confluent monolayers of endothelial cells in basal medium were preincubated for 24 hours in the presence or absence of phorbol myristate acetate (PMA, 100 ng/ml). MMP1 activity was measured using a spectrophotometric assay and western blotting. MMP2 and MMP9 were measured using zymography. TIMP1 was measured by enzyme linked immunosorbent assay and western blotting. Results-There was little diVerence between the amounts of MMP2 secreted by any of the cell lines. In response to PMA both synovial cell types showed a significantly higher MMP1 and MMP9 activity compared with FSE, although there was no diVerence between RASE and NSE. Tumour necrosis factor had minimal eVect on MMP activity. There was a striking decrease in the amount of TIMP1 secreted by RASE compared with normal synovium. Conclusions-As overall MMP activity is a balance between the amount of MMP and TIMP1 present, the low levels of TIMP1 produced by RASE would shift the balance in favour of increased MMP activity by these cells. This is likely to contribute to the angiogenic potential of RASE.

Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis

“…Interleukin-1 (IL-1), tumor necrosis factor ␣, and fibroblast growth factor promote MMP production, while transforming growth factor ␤, IL-6, IL-11, and leukemia inhibitory factor increase TIMP levels (28,44). These effects suggest that MMPs and TIMP are regulated differently, despite the fact that they are produced by the same cells within the joint (9), and a disproportionately low level of TIMP secretion may be part of the acquired functional abnormalities of RA synovial cells (47). In this study, serum levels of TIMP were significantly higher, but the TIMP:MMP ratios were significantly lower, in RA than in non-RA patients.…”

Adenovirus-based overexpression of tissue inhibitor of metalloproteinases 1 reduces tissue damage in the joints of tumor necrosis factor ? transgenic mice

“…However, in contrast to the overexpression of MMPs in RA, no up-regulation of TIMPs has been observed in RA synovial tissue (20,35), synovial fluid (25,27), or serum (39). This imbalance has been considered to be essential in the destructive events typical of RA (20,25,35,40,41). Therefore, and because synthetic inhibitors of MMPs have been successfully tested in T cell-driven models of arthritis (42,43) but have so far failed to improve human RA (44,45), we hypothesized that interventions leading to an overexpression of TIMPs, such as adenoviral gene transfer, could help to prevent structural damage in RA.…”

Update on synovitis

“…TIMPs and PAIs antagonize the effects of destructive enzymes. It has been confirmed recently that RA synovial endothelial cells produce decreased amounts of TIMP [54], which may, in part, account for the imbalance between MMPs and TIMP in RA. In addition, antiinflammatory cytokines, such as IL-4, IL-10, and IL-13 have been shown to inhibit MMP production.…”