This book presents the reader with an understanding of the role played by matrix metalloproteinases (MMPs) in the normal and diseased central nervous system (CNS). These enzymes may be important to brain development, and may also contribute to tissue destruction, which is observed with inflammatory and degenerative conditions of the brain. The book provides a background on the biology of MMPs, and on the stimuli and conditions that are linked to an increase in their production and activity. It describes the targets of MMPs, which include matrix proteins such as collagen, soluble cytokines and chemokines, and cell surface receptors. Studies implicating MMPs in neuronal process outgrowth and cell migration in CNS development are covered. The book also touches on studies suggesting that, in certain situations, dysregulated MMP activity and/or production may be critical to blood-brain barrier breakdown and neuronal damage./a
Abstract: Many diseases of the central nervous system share common pathophysiological processes, such as disruption of the blood-brain barrier (BBB), remodeling of the extracellular matrix (ECM), inflammation and oxidative stress. In the last two decades it has become evident that matrix metalloproteinases (MMPs) play an essential role in many of these processes. Several studies have focused on the regulation and expression of these proteases in experimental models of neurologic diseases, revealing that inhibition of MMPs in early stages of disease has the potential to reduce the extent of damage to nervous tissue and improve functional neurologic recovery. Research is currently focusing on defining the role of MMP in specific neurologic conditions to determine whether MMP inhibitors would be appropriate in clinical settings. Selective MMP inhibitors are currently used in research settings. However, commonly used drugs, such as corticosteroids and tetracyclines, are non selective MMPs inhibitors which are used in horses with neurologic disease. These drugs may alter the outcome of said disease by modification of MMP activity. This first part of this work, a review of MMP role in central nervous system diseases, has been made in attempt to translate some of the knowledge from human and laboratory species to the equine species and explore possible treatment options in horses affected by neurologic diseases. In the second part, we evaluated MMP-9 activity in the CSF of 40 horses affected by neurologic diseases. On gelatin zymography all horses had low but present MMP-9 activity.
This dissertation, "MT1-MMP Regulates Central Nervous System Development Through Notch Signaling" by Jin, Zhou, 周瑾, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: The central nervous system (CNS) development is a highly organized process involving cell proliferation, cell death and cell migration. The mechanisms that goven this process are complex and remain one of the most challenging question in neurobiology. Notch signaling is among the most important pathways that participate in the CNS development. The absence of Notch signaling causes precocious neuronal differentiation and reduced generation of neurons. On the contrary, activation of Notch signaling leads to the maintenance of embryonic telencephalic cells in an undifferentiated status. Moreover, Notch signaling first inhibits neuron fate while promotes glial fate and later promotes astroglia production and suppresses oligodendroglia differentiation. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is the first identified membrane tethered matrix metalloproteinase which is best and first known for its role in tumor metastasis. Since then, it has been shown that MT1-MMP is important for proper generation of many tissues and organs, such as the skeleton, lung or B-cells. In addition, MT1-MMP is also involved in several pathological conditions, particularly in cancer. It functions in extracellular matrix (ECM) turnover and membrane-anchored molecules cleavage hence it is important for cell-ECM interactions, soluble molecules releasing and cell signaling regulation. Indeed, recent findings showed that MT1-MMP sheds DLL1 to negatively regulate Notch signaling in bone marrow stroma cells (BMSCs) which ultimately causes defective B-cell development in MT1-MMP knockout mice. However, the function of MT1-MMP during CNS development has never been studied before. In this study, I hypothesize that MT1-MMP may be involved in CNS development and, together with the recent findings in our lab, its function may be mediated by Notch signaling. The expression pattern of MT1-MMP in CNS was for the first time described in this study. Loss of MT1-MMP affects CNS development with impaired ventricle development in forebrain and neural tube closure problem in the midbrain at embryonic stage. At postnatal stage, MT1-MMP loss causes enlarged lateral ventricle (LV) size, altered cortex pattern, accelerated cell death and defective differentiation into OLs. Furthermore, increased amount of Nestin+/GFAP+ cells in the MT1-MMP knockout as well as the larger size of the MT1-MMP-/- neurospheres were found, indicating that MT1-MMP participates in neural stem cell (NSC) and neural progenitor cell (NPC) proliferation, self-renewal and/or survival. DAPT treatment can rescue the phenotype of MT1-MMP-/- neurospheres and thus these results suggest that MT1-MMP controls CNS development through at least the regulation of Notch signaling. Notch signaling was demonstrated to be abnormally activated at both embryonic and postnatal stages as well as either in vivo or in vitro in the absence of MT1-MMP. Additional functions of MT1-MMP in the ECM and neuroepithelial cell (NEC) polarity can also be considered. The amount and distribution of the ECM component fibronectin and its main receptor β1-integrin are affected by loss of MT1-MMP. Besides, less primary cilium and cell surface accumulation of β-catenin and N-cadherin occurs in the MT1-MMP-/- neuroepithelium. In short, I found that MT1-MMP regulates Notch signaling in CNS. Indeed, loss of MT1-MMP causes abnormally activated Notch signaling that contributes to defective CNS de
This volume provides new advances regarding the involvement of MMPs in various diseases associated with inflammatory processes. Moreover, the recent development of selective and non selective inhibitors of MMPs give new insights in the relationship between activation of inflammatory cells and tissue remodelling and advise new therapeutics possibilities to the treatment of inflammatory disease. The volume has an international authorship and is written by leading experts in the field.
Cutting-edge investigators review the current status of the entire field, from the biology of MMPs through the current clinical studies. The authors include many leading scientists from pharmaceutical companies who present all the latest concepts and results on the preferred design strategies for MMP inhibitors, their molecular mechanisms, and their substrates. In addition, they fully describe their personal research on specific MMP inhibitors, detailing vanguard design strategies, their in vitro activity, the outcome of animal model studies and, where available, their toxicology, safety, efficacy in human clinical trials. Comprehensive and state-of-the-art, Matrix Metalloproteinase Inhibitors in Cancer Therapy offers basic and clinical investigators alike a richly informative summary of all the latest research on these powerful new drugs, and their high promise as emerging cancer therapeutics.
Multiple Sclerosis (MS) is an enigmatic immune mediated disease of the central nervous system that affects about 350,000 individuals in the US, and many more around the world. The mechanism of this disease is largely unknown and there is no cure for it. However, there are several well-characterized experimental animal models that help us understand and speculate about potential mechanisms of pathology in this disease. Many of the experimental therapies designed for this disease rely on testing the drugs in animal models before using it in clinical trials. This book combines for the first time the different experimental models for MS (including immune-mediated and viral) under one roof, and highlights aspects that are different or shared among these experimental models. It’s aim is to improve our understanding of this devastating disease and help us think about potential additional therapies for it.
