Abstract
IL-1beta is known promote cyclooxygenase-2 (COX- 2) and matrix metalloproteinase-2 (MMP-2) expression. This study focuses on the characterization of the signaling cascade associated with IL-1beta-induced matrix metalloproteinase-2 (MMP-2) regulation in human chondrocytes. The decrease in collagen levels in the conditioned media was prevented by a broad spectrum MMP inhibitor, suggesting that IL-1beta promotes the proteolytic process leading to MMP-2 activation. IL-1beta-related MMP-2 expression was found to be dependent on prostaglandin E2 (PGE2) production. In addition, the induction of COX-2 and MMP-2 was inhibited by the pretreatment of chondrocytes with a SB203580 or Ro 31-8220, indicating the involvement of protein kinase C (PKC) or p38 mitogen-activated protein kinase (MAPK). However, there is no cross-talk between PKC and p38 MAPK in the IL-1beta-induced MMP-2 activation. Taken together, these results demonstrated that IL-1beta induces MMP-2 expression through the PGE2-dependent mechanism in human chondrocytes.
Highlights
The regulation of chondrocyte metabolism is important for the maintenance of cartilage integrity
An effect which is suppressed by a cyclooxygenase (COX) inhibitor and is recovered by the addition of exogenous prostaglandin E2 (PGE2) suggests that PGE2 may mediate IL-1 and that the PGs may participate in the pathophysiology of cartilage destruction (Dingle et al, 1993; Blanco et al, 1999; Mifflin et al, 2002)
The matrix metalloproteinase (MMP)-2 has been proposed to participate in articular cartilage destruction and can be induced by a variety of oncogene products, mitogens, phorbol ester, and cytokines such as IL-1β and TNF-α (Tetlow et al, 2001; Okuno et al, 2002)
Summary
The regulation of chondrocyte metabolism is important for the maintenance of cartilage integrity. MMPs are implicated in the pathogenesis of inflammatory diseases of the articular chondrocytes (Chubinskaya et al, 1996; Nagase et al, 1999; Dreier et al, 2001; Tetlow et al, 2001), and are known to digest different components of the ECM during pathophysiologic turnover (Chai et al, 1997). The MMP-2 has been proposed to participate in articular cartilage destruction and can be induced by a variety of oncogene products, mitogens, phorbol ester, and cytokines such as IL-1β and TNF-α (Tetlow et al, 2001; Okuno et al, 2002). On binding to its receptor, IL-1β transduces signals that regulate gene expression (Geng et al, 1996) These signaling pathways include the mitogen activated protein kinase (MAPK) family, including extracellular signal-regulated kinase (ERK), c-Jun NH2terminal kinase and p38. The results we obtained indicate that IL-1β regulates MMP-2 through the participations of p38-dependent COX-2 expression
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