Metalloproteinases in biology and pathology of the nervous system

Abstract

Extracellular proteases are crucial regulators of cell function. The family of matrix metalloproteinases (MMPs) has classically been described in the context of extracellular matrix (ECM) remodelling, which occurs throughout life in diverse processes that range from tissue morphogenesis to wound healing. Recent evidence has implicated MMPs in the regulation of other functions, including survival, angiogenesis, inflammation and signalling. There are at least 25 members of the MMP family and, collectively, these proteases can degrade all constituents of the ECM. As a result of their potent proteolytic activity, abnormal MMP function can also lead to pathological conditions. The most widely studied disease that involves MMPs is cancer metastasis. In this case, the tumour cell is thought to use MMPs to overcome multiple structural barriers and establish a new focus of growth at a distant site from the primary tumour mass. In the nervous system, MMPs have also been associated with pathogenesis, particularly in multiple sclerosis (MS) and malignant gliomas 1 . A growing literature has linked MMPs to stroke, to Alzheimer's disease and to viral infections of the central nervous system (CNS). The goal of this review is to acquaint the reader with the biology of MMPs, particularly the functions of MMPs that are not associated with matrix turnover. We will highlight the roles of MMPs in pathology of the nervous system, and emphasize the fact that MMPs can also have physiological functions during CNS repair and ontogeny. Last, we will discuss the function of another group of metalloproteinases -ADAMs (a DISINTEGRIN and metalloproteinase) -in CNS pathophysiology, as these proteins might be responsible for many of the activities previously ascribed to MMPs. Metalloproteinases -the cast DISINTEGRINSPeptides found in the venoms of various snakes that inhibit the function of integrins of the β1 and β3 classes. 502 | JULY 2001 | VOLUME 2 www.nature.com/reviews/neuro R E V I E W S © 2001 Macmillan Magazines Ltd sion, sperm-egg fusion (for example, ADAM1 and -2), myoblast fusion (ADAM12) and the ectodomain shedding of cell-surface proteins (for example, ADAM9, -10 and -17). Most ADAMs have a prodomain, a metalloprotease region, a disintegrin domain for adhesion, a cysteine-rich region, epidermal-growth-factor (EGF) repeats, a transmembrane module and a cytoplasmic tail (FIG. 1). So, ADAMs are unique among cell-surface proteins in having both adhesive and proteolytic activities. The cysteine-rich region and EGF repeats are thought to mediate cell fusion or the interaction of ADAMs with other molecules such as chaperone proteins. The cytoplasmic tails of ADAM9 and -12 interact with protein kinase C and with src, respectively, implicating some ADAM family members as signalling molecules 5,6 . Although most ADAMs are transmembrane proteins, some members (for example, ADAM11, -12, -17 and -28) also have alternatively spliced forms that diverge before the transmembrane module to generate a soluble, secreted protein. It is important to not...

Matrix metalloproteinases in neuroinflammation

“…The growing ADAMs family includes enzymes that cleave a number of ECM molecules; they also act as "sheddases" in removing ectodomain molecules from the cell surface. Shedding of the TNF-␣ receptor, interleukin-6 (IL-6), L-selectin, and syndecans has been shown to be a function of ADAMs (Yong et al, 2001). ADAMs with a thrombospondin domain (ADAMTS) forms another group of MPs.…”

“…Conversely, when the inhibitors are excessively expressed, and proteolysis is restricted, there is a buildup of the ECM proteins with fibrosis. Several recent reviews have been written on the role of the MMPs in brain, including information on the ADAMs family (Romanic and Madri, 1994;Rosenberg, 1995;Yong et al, 1998Yong et al, , 2001Mun-Bryce and Rosenberg, 1998b;Lukes et al, 1999). The focus of this review is on studies of the role of MPs in the neuroinflammation of brain ischemia.…”

Leptin induces migration and invasion of glioma cells through MMP‐13 production

“…MMPs play a central role in tumor invasion due to their ability to degrade many extracellular matrix (ECM) components and other substrates (Ala-aho and Kahari 2005), and tumor cells consequently invade into the surrounding stroma consisting primarily of fibrillar 5 GLIA- collagens. The MMPs can be divided into subgroups of collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and other MMPs according to their substrate specificity and function (Yong et al 2001). MMP-13 is a collagenolytic MMP characterized by a wide substrate specificity, and it is expressed by many types of invasive tumors, such as breast carcinomas (Freije et al 1994), squamous cell carcinomas of the head and neck (Leivonen et al 2006).…”

Hypoxia-controlled matrix metalloproteinase-9 hyperexpression promotes behavioral recovery after ischemia

“…It is up-regulated in the fi rst 3 days after stroke (acute phase) in mouse brain, contributing to bloodbrain barrier (BBB) permeability and brain infl ammation [15,16] .…”

“…These lines of evidence suggest that strategies to modulate MMP-9 expression at different stages are needed to promote post-stroke recovery. We hypothesized that lentivirus-mediated MMP-9 gene therapy may provide a useful approach for stroke treatment in the sub-acute phase, but uncontrolled MMP-9 expression may induce BBB disruption and brain hemorrhage [15,16,19] . Therefore, the safe control of exogenous MMP-9 expression is extremely important.…”