Extracellular matrix degradation by metalloproteinases and central nervous system diseases
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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 inbalance 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.
Index EntriesBlood-brain barrier brain tumors cerebral ischemia extracellular matrix matrix metalloproteinases
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- Agarwall C., Hembree J. R., Rorke E. A., and Eckert R. L. (1994) Transforming growth factor β1 regulation of metalloproteinase production in cultured human cervical epithelial cells.Cancer res. 54, 943–949.Google Scholar
- Delany A. M. and Brinckerhoff C. E. (1992) Posttranscriptional regulation of collagenase and stromelysin gene expression by epidermal growth factor and dexamethasone in cultured human fibroblasts.J. Cell. Biochems. 50, 400–410.Google Scholar
- Edvardsen K., Chen W., Rucklidge G. J., Walsh F. S., Obrink B., and Bock E. (1993) Transmembrane neural cell-adhesion molecule (NCAM), but not glycosyl-phosphatidylinositol-anchored NCAM, down-regulates secretion of matrix metalloproteinases.Proc. Natl. Acad. Sci. USA 90, 11,463–11,467.Google Scholar
- Gottschall P. E. (1995) Cytokines regulates gelatinase A and B (matrix metalloproteinase 2 and 9) activity in cultured rat astrocytes.J. Neurochem. 64, 1524–1535.Google Scholar
- Lee S. C., Liu W., Dickson D. W., Brosnan C. F., and Berman J. W. (1997) Cytokine production by human fetal microglia and astrocytes.J. Immunol. 150, 2659–2667.Google Scholar
- Liesi P., Kaakkola S., Dahl D., and Vaheri A. (1984) Laminin is induced in astrocytes of adult brain by injury.EMBO J. 3, 68–686.Google Scholar
- Rosenberg G. A. (1995) Matrix metalloproteinases in brain injury.J. Neurotrauma 12, 151–155.Google Scholar
- Strongin Y. A., Marmer B. L., Grant G. A., and Goldberg G. I. (1993) Plasma-membrane dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2.J. Biol. Chem. 268, 14,033–14,039.Google Scholar
- Vlodavsky I., Ishai-Michaeli R., Atzmon R., Mohsen M., Levi E., Bar-Shavit R., et al. (1992) Extracellular sequestration and release of fibroblast growth factor: A possible mechanism for indirect angiogenesis, inGrowth Factors of the Vascular and Nervous System. International Symposium on Biotechnology of Growth Factors, Milan, May 1991 (Lenfant C., Paoletti R., and Albertini A., eds.), Karger, Basel, pp. 38–47.Google Scholar