Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases

Abstract

Cellular functions within tissues are strictly regulated by the tissue microenvironment which comprises extracellular matrix and extracellular matrix-deposited factors such as growth factors, cytokines and chemokines. These molecules are metabolized by matrix metalloproteinases (MMP), a disintegrin and metalloproteinases (ADAM) and ADAM with thrombospondin motifs (ADAMTS), which are members of the metzincin superfamily. They function in various pathological conditions of both neoplastic and non-neoplastic diseases by digesting different substrates under the control of tissue inhibitors of metalloproteinases (TIMP) and reversion-inducing, cysteine-rich protein with Kazal motifs (RECK). In neoplastic diseases MMP play a central role in cancer cell invasion and metastases, and ADAM are also important to cancer cell proliferation and progression through the metabolism of growth factors and their receptors. Numerous papers have described the involvement of these metalloproteinases in non-neoplastic diseases in nearly every organ. In contrast to the numerous review articles on their roles in cancer cell proliferation and progression, there are very few articles discussing non-neoplastic diseases. This review therefore will focus on the properties of MMP, ADAM and ADAMTS and their implications for non-neoplastic diseases of the cardiovascular system, respiratory system, central nervous system, digestive system, renal system, wound healing and infection, and joints and muscular system.

Figure 1

Domain structures of matrix metalloproteinases (MMP), a disintegrin and metalloproteinases (ADAM), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS). MMP are classified into two categories, secreted-type MMP and membrane-anchored MMP. The general structure of MMP consists of a propeptide domain (P), a metalloproteinase domain (MP) and a C-terminal, hemopexin-like domain (HP). Gelatinases have an additional insertion of collagen-binding type II, repeats of fibronectin (Cb) in the MP domain, whereas matrilysins lack an HP domain. Furin-activated MMP contain an RKRR sequence (furin-recognition site) (F) at the end of the propeptide. Membrane-anchored MMP are composed of type I transmembrane-type MMP, glycosylphosphatidylinositol (GPI)-linked MMP and type II transmembrane-type MMP, all of which have furin-recognition sites. Like MMP, the ADAM gene family members are divided into secreted ADAMTS and membrane-anchored ADAM. ADAMTS have a basic structure of a propeptide domain (P), a furin-recognition site (F), a metalloproteinase domain (MP), a disintegrin domain (DIS), thrombospondin motifs (TS), a cysteine-rich domain (CR) and a spacer domain (SP). Most ADAMTS, except for ADAMTS4, have an additional 1–14 TS attached to the end of SP. The ADAM are composed of a propeptide domain (P), a furin-recognition site (F), a metalloproteinase domain (MP), a disintegrin domain (DIS), a cysteine-rich domain (CR), transmembrane domain (TM) and cytoplasmic domain (CD). Both ADAMTS and ADAM have large propeptide domains (P), which are considered to play a role in initial protein folding and to keep the catalytic activity in check during intracellular trafficking. EGF, epidermal growth factor; N, NH2-terminal; C, COOH-terminal; MT, membrane-type; Zn, zinc.

Figure 2

Role of matrix metalloproteinases (MMP) in atherosclerosis and aneurysm formation. Studies using Apolipoprotein-E (Apoe) knockout mice have demonstrated that MMP expressed in the atheroma are present mainly in macrophages but also in other cells critical in medial degeneration, such as endothelial cells and smooth muscle cells. Oxidized (ox) low-density lipoprotein (LDL), reactive oxygen species (ROS), inflammatory cytokines, and CD40 ligand are major inducers of MMP expression in the atheroma. Gene knockouts in either MMP-2, −3, −9, −12 or −14 conferred resistance to microaneurysm formation, and uPA-generated plasmin is a key activator of MMP in this process. MMP also contribute to the development of the atherosclerotic lesion, playing a detrimental (MMP-2, −8, −12, −14) or protective role (MMP-1 and −3). MMP-13 contributes to collagen content and organization in the atheroma, while the role of MMP-9 in atherosclerosis is controversial.

Figure 3

Role of matrix metalloproteinases (MMP) in emphysema and acute respiratory distress syndrome (ARDS). In patients with emphysema (left panel), MMP-1 is expressed in epithelial cells, especially type II pneumocytes stimulated by cigarette smoke. MMP-12 produced by macrophages is involved in the regulation of inflammation. MMP-8 and MMP-9 are secreted mainly from neutrophils in response to inflammatory stimuli including IL-17 produced by lymphocytes. In ARDS (right panel), increased levels of MMP-2, MMP-8, MMP-9 and tissue inhibitors of metalloproteinases (TIMP)-1 are observed under inflammatory conditions such as sepsis and systemic inflammatory response syndrome (SIRS). Hyperoxia also stimulates macrophages to produce MMP-2 and MMP-9. IL-6 has been shown to upregulate TIMP-1 expression.

Figure 4

Effects of matrix metalloproteinases (MMP), a disintegrin and metalloproteinases (ADAM), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTS) and their involvement in biological and pathological conditions. These metalloproteinases induce various cellular effects through the metabolism of the extracellular matrix (ECM) and non-ECM molecules. The highly regulated action of the proteinases is critical to biological function, but uncontrolled and excessive activity is implicated in various pathological conditions in both neoplastic and non-neoplastic diseases. Regulated intramembrane proteolysis (RIPping).