Extracellular matrix degradation by metalloproteinases and central nervous system diseases

Abstract

Matrix metalloproteinases (MMPs) are a gene family of neutral proteases involved in normal and pathological processes in the central nervous system (CNS). Normally released into the extracellular space, MMPs break down the extracellular matrix (ECM) to allow cell growth and to facilitate remodeling. Proteolysis becomes pathological when the normal balance between the proteases and their inhibitors, tissue inhibitors to metalloproteinases (TIMPs), is lost. Cancer cells secrete neutral proteases to facilitate spread through the ECM. MMPs increase capillary permeability, and they have been implicated in demyelination. Neurological diseases, such as brain tumors, multiple sclerosis, Guillain-Barré, ischemia, Alzheimer's disease, and infections, lead to an increase in the matrix-degrading proteases. Two classes of neutral proteases have been extensively studied, namely the MMPs and the plasminogen activators (PAs), which act in concert to attack the ECM. After proteolytic injury occurs, the process of ECM remodeling begins, which can lead to fibrosis of blood vessels and gliosis. TIMPs are increased after the acute injury and may add to the fibrotic buildup of ECM components. Thus, an imbalance in proteolytic activity either during the acute injury or in recovery may aggravate the underlying disease process. Agents that affect the proteolytic process at any of the regulating sites are potentially useful in therapy.

The extracellular matrix in multiple sclerosis: an update

“…MMPs also mediate a wide range of proteolytic activities that facilitate leukocyte migration and activation within the CNS parenchyma and directly degrade myelin components (12)(13)(14). Their presence and activities in cerebrospinal fluid of MS patients correlate with clinical disease activity (15)(16)(17) and MMP inhibition is a potential mode of MS treatment currently being investigated (18).…”

Matrix metalloproteinases in neuroinflammation

“…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.…”

Molecular Mechanisms of Tumor Angiogenesis

“…It is conceivable that inhibition of VEGF and other relevant angiogenic cytokines will eliminate the www.intechopen.com angiogenic survival response post-RT, radiosensitizing ECs and potentiating the benefits of RT. The above results are supported to an extent by recent in vivo studies 120,121,123,128 , however, unfortunately clinical trials involving combination of RT and anti-VEGF therapy have not proven beneficial, suggesting other mechanisms regulating tumor neovascularization in response to RT may be involved 34,37,39,48 . Recent evidence has demonstrated the specific migration and recruitment of BMDCs to the site of radiation specifically, although negates the process of differentiation following integration.…”

“…The precise timing of this window of opportunity and extent by which 'vascular normalization' improves response to RT however remains unknown. There are some preclinical studies and early clinical trials that have explored the therapeutic benefits of combining anti-angiogenesis with RT, but results have been inconsistent 34,[37][38][39][40][41][42][43][44][45][46][47][48] and the optimal scheduling of these adjuvant treatments has to be established. Moreover, individual tumor type plays a significant role in determining the correct combinatorial scheduling and very few studies have focused on brain tumors.…”

“…The basement membrane provides structural support to the vasculature and is composed of type IV collagen, laminin and fibronectin 38 . Proteases such as Matrix Metalloproteinases (MMPs), and their tissue inhibitors, (TIMPs), regulate the breakdown of ECM and are associated with tissue destruction in many pathologic settings [38][39][40] . The relative contribution of individual MMPs to vessel formation is not precisely understood, however, certain MMPs are thought to have a more specific angiogenic regulatory role, in particular MMP-2 (gelatinaseA) and MMP-9 (gelatinaseB) both cleave collagen type IV, fibronectin and laminin, the major components of blood vessel basement membrane 41 .…”