MMPs include interstitial collagenases, which cleave fibrillar collagen (MMP-1,-2 and -3); gelatinases (MMP-2 and 9), which degrade amorphous collagen and fibronectin; and stromelysins (MMP-3, -10, and -11), which degrade a variety of ECM constituents, including proteoglycans, laminin, fibronectin, and amorphous collagen. Matrix metalloproteinase regulation. The four mechanisms shown include (1) regulation of synthesis by a variety of growth factors or cytokines, (2) inhibition of synthesis by corticosteroids or transforming growth factor β (TGF-β), (3) regulation of the activation of the secreted but inactive precursors, and (4) blockade of the enzymes by specific tissue inhibitors of metalloproteinases (TIMPs). ECM, Extracellular matrix; EGF, epidermal growth factor; IL-1, interleukin 1; PDGF, platelet-derived growth factor; TNF, tumor necrosis factor. (Modified from Matrisian LM: Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 6:122, 1990.)
MMPs, or matrix metalloproteinases, are a group of enzymes that play a crucial role in the remodeling and degradation of the extracellular matrix (ECM). The ECM is a complex network of proteins, including collagen, fibronectin, and proteoglycans, that provides structural support for tissues and organs.
There are several types of MMPs, each with different substrates and functions. For example, interstitial collagenases (MMP-1, -2, and -3) specifically cleave fibrillar collagen, which is the main structural component of connective tissues such as tendons and cartilage. Gelatinases (MMP-2 and -9) degrade amorphous collagen and fibronectin, which are components of the ECM. Stromelysins (MMP-3, -10, and -11) have a broader range of substrates and can degrade proteoglycans, laminin, fibronectin, and amorphous collagen.
The activity of MMPs needs to be tightly regulated to prevent excessive ECM degradation, which can lead to tissue damage and contribute to various diseases. MMP regulation can occur through several mechanisms:
1. Regulation of synthesis: MMP synthesis can be stimulated by various growth factors or cytokines, such as epidermal growth factor (EGF), interleukin 1 (IL-1), and platelet-derived growth factor (PDGF). These factors can increase the production of MMPs, leading to increased ECM degradation.
2. Inhibition of synthesis: Corticosteroids and transforming growth factor β (TGF-β) can inhibit the synthesis of MMPs. This helps to prevent excessive ECM degradation and maintain tissue integrity.
3. Regulation of activation: MMPs are typically secreted in an inactive form called zymogens or pro-MMPs. Activation of these pro-MMPs is regulated by specific mechanisms, including proteolytic cleavage by other enzymes or interaction with other molecules. This ensures that MMPs are only activated when necessary.
4. Inhibition by tissue inhibitors of metalloproteinases (TIMPs): TIMPs are endogenous molecules that can bind to and inhibit the activity of MMPs. They act as natural inhibitors, preventing excessive ECM degradation and maintaining tissue homeostasis.
Overall, the regulation of MMP activity is critical for maintaining the balance between ECM remodeling and tissue integrity. Dysregulation of MMPs can contribute to pathological conditions such as cancer invasion, arthritis, and tissue fibrosis.