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Extracellular matrix degradation by metalloproteinases and central nervous system diseases
A Lukes1, S Mun-Bryce, M Lukes
1Department of Neurology, University of New Mexico School of Medicine, Albuquerque, USA. anton.lukes@insel.ch
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.
Insights
Matrix metalloproteinases (MMPs), crucial for the central nervous system (CNS), can cause pathological damage when their balance with inhibitors is lost. Targeting these proteases offers potential therapeutic strategies for neurological diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Matrix metalloproteinases (MMPs) are neutral proteases vital for extracellular matrix (ECM) remodeling in the central nervous system (CNS).
- An imbalance between MMPs and their inhibitors (TIMPs) disrupts normal CNS function and contributes to pathological processes.
- MMPs are implicated in cancer cell spread, increased capillary permeability, and demyelination.
Purpose of the Study:
- To review the role of MMPs and plasminogen activators (PAs) in neurological diseases.
- To highlight the pathological consequences of proteolytic imbalance in the CNS.
- To explore the therapeutic potential of targeting proteolytic processes.
Main Methods:
- Literature review of MMPs and PAs in CNS disorders.
- Analysis of the interplay between proteases and their inhibitors (TIMPs).
- Examination of ECM remodeling following proteolytic injury.
Main Results:
- Elevated MMP levels are observed in various neurological conditions including brain tumors, multiple sclerosis, and Alzheimer's disease.
- Proteolytic imbalance contributes to ECM remodeling, fibrosis, and gliosis.
- MMPs facilitate cancer cell invasion and demyelination.
Conclusions:
- Dysregulation of MMPs and PAs significantly contributes to the pathogenesis of neurological diseases.
- Therapeutic interventions targeting the proteolytic system hold promise for treating CNS disorders.
- Restoring the balance between MMPs and TIMPs is a key therapeutic goal.