The extracellular matrix (ECM) is a highly dynamic structure present in all tissues that undergoes a process of continuous controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as matrix metalloproteinases (MMPs). The ECM functions as a physical support for tissue integrity and elasticity and acts dynamically to control tissue homeostasis. The functional importance of the ECM is illustrated by the wide range of tissue defects or, in severe cases, the embryonic lethality caused by mutations in genes that encode components of the ECM.
Components of the ECM constantly interact with surrounding cells by serving as ligands for cell receptors such as integrins, thereby transmitting signals that regulate adhesion, migration, proliferation, apoptosis, survival or differentiation. The ECM can also sequester and locally release growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF) and other signalling molecules. ECM components released through ECM cleavage also regulate ECM architecture and influence cell behaviour. Moreover, cells are constantly rebuilding and remodelling the ECM through synthesis, degradation, reassembly and chemical modification. These processes are tightly regulated in order to maintain tissue homeostasis, particularly in response to injury.
During ECM remodelling many of the ECM components are cleaved and broken down to regulate ECM abundance, composition and structure as well as to release biologically active molecules into the microenvironment. The ECM can be cleaved by different families of proteases.
Matrix metalloproteinases (MMPs) are the main enzymes involved in ECM degradation. MMPs show low activity levels under normal physiological conditions, but this is increased during repair or remodelling processes and in diseased or inflamed tissue. Most MMPs are secreted as zymogens and activated within the extracellular space. Collectively, MMPs can degrade all ECM proteins and their proteolytic actions on the ECM have crucial roles in organogenesis and branching morphogenesis.
Aberrant MMP activity is a feature of a number of diseases and elevated levels of MMP-3 in different tissues is considered symptomatic of different diseases. Within the CNS high levels of active MMP-3 have recently been proposed as a biomarker for AD, mutations in MMP-3 have been associated with a range of cancers, and increased MMP-3 levels in the synovial membrane are considered indicative of rheumatoid arthritis and offer information on the disease prognosis.
A recent study has identified the signalling events that give rise to increased levels of MMP-3 and the damage this causes within the joints of patients with rheumatoid arthritis. Synovial fibroblasts co-cultured with B cells were seen to secrete increased levels of MMP-3, IL-6 and IL-8 in response to the production of TNF-? and IL-1? by B cells. The synovial fibroblasts activated in this manner by B cells were able to invade human cartilage in a SCID mouse fibroblast invasion model in vivo, demonstrating their aggressive potential to destroy cartilage and bone tissue in rheumatoid arthritis.
Targeting the ECM and the enzymes that remodel it is relatively unexplored in terms of new treatments, yet many drug discovery teams perceive the ECM as a barrier to efficacious drug action rather than a therapeutic target. Indeed, strategies for developing therapeutic antibodies to targets within the ECM have not gained much favour, often perceived as weak and unspecific. A major problem with targeting the molecules of the ECM is the ability to specifically target the desired site without causing undesired side effects. To improve these therapies and offer new hope to the many patients suffering with the increasing number of diseases that show an association with the ECM more research is needed to unpick the function of this signalling network.