Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Metalloproteinases: Mediators of Pathology and Regeneration in the CNS

Key Points

  • The matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) are expressed in the healthy nervous system, although many of them are significantly upregulated in disease and injury states. The substantial upregulation of several metalloproteinases is detrimental and contributes to neuroinflammation and neuropathology in diseases and insults, including multiple sclerosis, stroke and spinal cord injury.

  • This review discusses some of the general functions of metalloproteinases in mediating responses to neurological disease state. It highlights the interactions of metalloproteinases with other molecules found at injury sites, such as chemokines and nitric oxide, which generate products that have profound effects on the nervous system.

  • In contrast to their detrimental functions, it is now clear that some metalloproteinases have beneficial roles during development and after injury to the adult nervous system. This review summarizes the evidence and discusses the mechanisms by which metalloproteinases regulate neurogenesis, axonal guidance and growth in neural development.

  • In response to injury, and following the initial abnormal upregulation of several metalloproteinases, some metalloproteinases are expressed very locally at particular sites at specific time points after the insult. Often, the levels of these discretely expressed metalloproteinases are low and difficult to detect with gel-based approaches. In these circumstances, these metalloproteinases might participate in the repair process. This review discusses the data suggesting that MMPs are involved in axonal regeneration, and evaluates some of the attendant mechanisms. The latter includes interference with inhibitors of axonal regrowth, which are present in CNS myelin, including Nogos. The clearance of inhibitory extracellular matrix proteins constitutes another mechanism by which metalloproteinases regulate axonal regrowth.

  • Metalloproteinases also participate in the remyelination process following injury, and the evidence for this is reviewed here.

  • In view of the beneficial and detrimental roles of metalloproteinases, this review discusses the determinants through which the different outcomes are achieved.

  • We speculate that acute neurological diseases and insults, including stroke and spinal cord injury, are amenable to treatment with metalloproteinase inhibitors, given that the acute upregulation of several metalloproteinases leads to significant neuropathology. However, the potential use of metalloproteinase inhibitors in chronic conditions such as multiple sclerosis should be approached with caution, because of the beneficial roles of metalloproteinases in some of the repair processes.

  • Significant challenges still lie ahead with respect to modulating metalloproteinase functions in development and following an insult or in disease. Nonetheless, studies of CNS regeneration must consider the metalloproteinases, given their multitude of beneficial and detrimental functions in the nervous system.

Abstract

The matrix metalloproteinases and related A disintegrin and metalloproteinase enzymes are implicated in various diseases of the nervous system. However, metalloproteinases are increasingly being recognized as having beneficial roles during nervous system development and following injury. This review discusses general principles that govern the expression of metalloproteinases in the nervous system and their detrimental outcomes. It then focuses on the roles of metalloproteinases and their mechanisms in regulating neurogenesis, myelin formation and axonal growth. It is clear that metalloproteinases are important determinants in enabling recovery from injury to the nervous system.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Structure of matrix metalloproteinases and A disintegrin and metalloproteinases.
Figure 2: Interactions between metalloproteinases, cytokines, chemokines and other molecules present at a site of injury and their consequences.
Figure 3: The metalloproteinases regulate developmental and regenerative events in the CNS.
Figure 4: Mechanisms by which metalloproteinases might regulate axonal regeneration of neurons.
Figure 5: Metalloproteinases regulate myelinogenesis.
Figure 6: Multiple ways of targeting the metalloproteinases.

References

  1. Sternlicht, M. D. & Werb, Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463–516 (2001). A very thorough review on the many roles of metalloproteinases.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Dumin, J. A. et al. Pro-collagenase-1 (matrix metalloproteinase-1) binds the α2β1 integrin upon release from keratinocytes migrating on type I collagen. J. Biol. Chem. 276, 29368–29374 (2001).

    CAS  PubMed  Article  Google Scholar 

  3. Yu, W. H., Woessner, J. F. Jr, McNeish, J. D. & Stamenkovic, I. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev. 16, 307–323 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Mott, J. D. & Werb, Z. Regulation of matrix biology by matrix metalloproteinases. Curr. Opin. Cell Biol. 16, 558–564 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. McCawley, L. J. & Matrisian, L. M. Matrix metalloproteinases: they're not just for matrix anymore! Curr. Opin. Cell Biol. 13, 534–540 (2001).

    CAS  Article  PubMed  Google Scholar 

  6. Parks, W. C., Wilson, C. L. & Lopez-Boado, Y. S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nature Rev. Immunol. 4, 617–629 (2004). This review introduces many aspects of MMPs and links the fields of inflammation and metalloproteinase biology in a cohesive manner.

    CAS  Article  Google Scholar 

  7. Overall, C. M. & Lopez-Otin, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Rev. Cancer 2, 657–672 (2002).

    CAS  Article  Google Scholar 

  8. White, J. M. ADAMs: modulators of cell–cell and cell–matrix interactions. Curr. Opin. Cell Biol. 15, 598–606 (2003).

    CAS  PubMed  Article  Google Scholar 

  9. Blobel, C. P. ADAMs: key components in EGFR signalling and development. Nature Rev. Mol. Cell Biol. 6, 32–43 (2005). This review considers several aspects of protein ectodomain shedding and discusses several mechanistic aspects of metalloproteinase biology.

    CAS  Article  Google Scholar 

  10. Murphy, G. et al. Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis: the specificity is in the detail. Biochem. Soc. Symp. 70, 65–80 (2003).

    CAS  Article  Google Scholar 

  11. Baker, A. H., Edwards, D. R. & Murphy, G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J. Cell Sci. 115, 3719–3727 (2002).

    CAS  PubMed  Article  Google Scholar 

  12. Porter, S., Clark, I. M., Kevorkian, L. & Edwards, D. R. The ADAMTS metalloproteinases. Biochem. J. 386, 15–27 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Brundula, V., Rewcastle, N. B., Metz, L. M., Bernard, C. C. & Yong, V. W. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 125, 1297–1308 (2002).

    PubMed  Article  Google Scholar 

  14. Weaver, A. et al. An elevated matrix metalloproteinase in experimental autoimmune encephalomyelitis is protective by affecting Th1/Th2 polarization. FASEB J. 19, 1668–1670 (2005).

    CAS  PubMed  Article  Google Scholar 

  15. Karkkainen, I., Rybnikova, E., Pelto-Huikko, M. & Huovila, A. P. Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS. Mol. Cell. Neurosci. 15, 547–560 (2000). The first article to emphasize that several metalloproteinases, particularly those of the ADAM family, are found in the CNS.

    CAS  PubMed  Article  Google Scholar 

  16. Yong, V. W., Power, C., Forsyth, P. & Edwards, D. R. Metalloproteinases in biology and pathology of the nervous system. Nature Rev. Neurosci. 2, 502–511 (2001). Contains a comprehensive list of the detrimental roles of metalloproteinases in the nervous system, and summarizes the roles of metalloproteinases in several neurological diseases.

    CAS  Article  Google Scholar 

  17. Lo, E. H., Wang, X. & Cuzner, M. L. Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloproteinases. J. Neurosci. Res. 69, 1–9 (2002).

    CAS  PubMed  Article  Google Scholar 

  18. Cunningham, L. A., Wetzel, M. & Rosenberg, G. A. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50, 329–339 (2005).

    PubMed  Article  Google Scholar 

  19. Wells, J. E., Hurlbert, R. J., Fehlings, M. G. & Yong, V. W. Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 126, 1628–1637 (2003).

    PubMed  Article  Google Scholar 

  20. Toft-Hansen, H., Nuttall, R. K., Edwards, D. R. & Owens, T. Key metalloproteinases are expressed by specific cell types in experimental autoimmune encephalomyelitis. J. Immunol. 173, 5209–5218 (2004).

    CAS  PubMed  Article  Google Scholar 

  21. Bar-Or, A. et al. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain 126, 2738–2749 (2003).

    PubMed  Article  Google Scholar 

  22. Power, C. et al. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann. Neurol. 53, 731–742 (2003).

    CAS  PubMed  Article  Google Scholar 

  23. Wells, J. E. et al. An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J. Neurosci. 23, 10107–10115 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Opdenakker, G. et al. Gelatinase B functions as regulator and effector in leukocyte biology. J. Leukoc. Biol. 69, 851–859 (2001).

    CAS  PubMed  Google Scholar 

  25. Noble, L. J., Donovan, F., Igarashi, T., Goussev, S. & Werb, Z. Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J. Neurosci. 22, 7526–7535 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Larsen, P. H., Wells, J. E., Stallcup, W. B., Opdenakker, G. & Yong, V. W. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J. Neurosci. 23, 11127–11135 (2003). The first report to emphasize that some MMPs, which are upregulated after injuries to the adult CNS, can have beneficial functions.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Esparza, J., Kruse, M., Lee, J., Michaud, M. & Madri, J. A. MMP-2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP-9 expression and activity. FASEB J. 18, 1682–1691 (2004).

    CAS  PubMed  Article  Google Scholar 

  28. Waubant, E. et al. Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology 53, 1397–1401 (1999).

    CAS  PubMed  Article  Google Scholar 

  29. Correale, J. & de los Milagros Bassani Molinas, M. Temporal variations of adhesion molecules and matrix metalloproteinases in the course of MS. J. Neuroimmunol. 140, 198–209 (2003).

    CAS  PubMed  Article  Google Scholar 

  30. Fiotti, N. et al. MMP-9 microsatellite polymorphism and multiple sclerosis. J. Neuroimmunol. 152, 147–153 (2004).

    CAS  PubMed  Article  Google Scholar 

  31. Kieseier, B. C., Pischel, H., Neuen-Jacob, E., Tourtellotte, W. W. & Hartung, H. P. ADAM-10 and ADAM-17 in the inflamed human CNS. Glia 42, 398–405 (2003).

    PubMed  Article  Google Scholar 

  32. Goertsches, R., Comabella, M., Navarro, A., Perkal, H. & Montalban, X. Genetic association between polymorphisms in the ADAMTS14 gene and multiple sclerosis. J. Neuroimmunol. 164, 140–147 (2005).

    CAS  PubMed  Article  Google Scholar 

  33. Pagenstecher, A., Stalder, A. K., Kincaid, C. L., Shapiro, S. D. & Campbell, I. L. Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states. Am. J. Pathol. 152, 729–741 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gottschall, P. E. & Deb, S. Regulation of matrix metalloproteinase expressions in astrocytes, microglia and neurons. Neuroimmunomodulation 3, 69–75 (1996).

    CAS  PubMed  Article  Google Scholar 

  35. Vecil, G. G. et al. Interleukin-1 is a key regulator of matrix metalloproteinase-9 expression in human neurons in culture and following mouse brain trauma in vivo. J. Neurosci. Res. 61, 212–224 (2000).

    CAS  PubMed  Article  Google Scholar 

  36. Le, D. M. et al. Exploitation of astrocytes by glioma cells to facilitate invasiveness: a mechanism involving matrix metalloproteinase-2 and the urokinase-type plasminogen activator-plasmin cascade. J. Neurosci. 23, 4034–4043 (2003).

    PubMed  Article  PubMed Central  Google Scholar 

  37. Rosenberg, G. A. et al. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res. 893, 104–112 (2001).

    CAS  PubMed  Article  Google Scholar 

  38. Gu, Z. et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002). Reveals a mechanism by which metalloproteinases regulate cell death.

    CAS  PubMed  Article  Google Scholar 

  39. McQuibban, G. A. et al. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 289, 1202–1206 (2000).

    CAS  PubMed  Article  Google Scholar 

  40. Van den Steen, P. E., Proost, P., Wuyts, A., Van Damme, J. & Opdenakker, G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-α and leaves RANTES and MCP-2 intact. Blood 96, 2673–2681 (2000).

    CAS  PubMed  Google Scholar 

  41. Li, Q., Park, P. W., Wilson, C. L. & Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635–646 (2002).

    CAS  PubMed  Article  Google Scholar 

  42. Zhang, K. et al. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nature Neurosci. 6, 1064–1071 (2003).

    CAS  Article  PubMed  Google Scholar 

  43. Anthony, D. C. et al. Matrix metalloproteinase expression in an experimentally-induced DTH model of multiple sclerosis in the rat CNS. J. Neuroimmunol. 87, 62–72 (1998).

    CAS  PubMed  Article  Google Scholar 

  44. Newman, T. A. et al. T-cell- and macrophage-mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases. Brain 124, 2203–2214 (2001).

    CAS  PubMed  Article  Google Scholar 

  45. Proost, P., Van Damme, J. & Opdenakker, G. Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic protein. Biochem. Biophys. Res. Commun. 192, 1175–1181 (1993).

    CAS  PubMed  Article  Google Scholar 

  46. Ito, A. et al. Degradation of interleukin 1β by matrix metalloproteinases. J. Biol. Chem. 271, 14657–14660 (1996).

    CAS  PubMed  Article  Google Scholar 

  47. Zalewska, T., Ziemka-Nalecz, M., Sarnowska, A. & Domanska-Janik, K. Involvement of MMPs in delayed neuronal death after global ischemia. Acta Neurobiol. Exp. (Wars.) 62, 53–61 (2002).

    Google Scholar 

  48. Bridges, L. C. & Bowditch, R. D. ADAM–integrin interactions: potential integrin regulated ectodomain shedding activity. Curr. Pharm. Des. 11, 837–847 (2005).

    CAS  PubMed  Article  Google Scholar 

  49. Chintala, S. K., Zhang, X., Austin, J. S. & Fini, M. E. Deficiency in matrix metalloproteinase gelatinase B (MMP-9) protects against retinal ganglion cell death after optic nerve ligation. J. Biol. Chem. 277, 47461–47468 (2002).

    CAS  PubMed  Article  Google Scholar 

  50. Jourquin, J. et al. Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate. Eur. J. Neurosci. 18, 1507–1517 (2003).

    PubMed  Article  Google Scholar 

  51. Zhang, X., Cheng, M. & Chintala, S. K. Kainic acid-mediated upregulation of matrix metalloproteinase-9 promotes retinal degeneration. Invest. Ophthalmol. Vis. Sci. 45, 2374–2383 (2004).

    PubMed  Article  Google Scholar 

  52. Vos, C. M. et al. Cytotoxicity by matrix metalloprotease-1 in organotypic spinal cord and dissociated neuronal cultures. Exp. Neurol. 163, 324–330 (2000).

    CAS  PubMed  Article  Google Scholar 

  53. Conant, K. et al. Matrix metalloproteinase 1 interacts with neuronal integrins and stimulates dephosphorylation of Akt. J. Biol. Chem. 279, 8056–8062 (2004).

    CAS  PubMed  Article  Google Scholar 

  54. Frolichsthal-Schoeller, P. et al. Expression and modulation of matrix metalloproteinase-2 and tissue inhibitors of metalloproteinases in human embryonic CNS stem cells. Neuroreport 10, 345–351 (1999).

    CAS  PubMed  Article  Google Scholar 

  55. Heine, W., Conant, K., Griffin, J. W. & Hoke, A. Transplanted neural stem cells promote axonal regeneration through chronically denervated peripheral nerves. Exp. Neurol. 189, 231–240 (2004).

    CAS  PubMed  Article  Google Scholar 

  56. Jaworski, D. M. & Fager, N. Regulation of tissue inhibitor of metalloproteinase-3 (Timp-3) mRNA expression during rat CNS development. J. Neurosci. Res. 61, 396–408 (2000).

    CAS  PubMed  Article  Google Scholar 

  57. Perez-Martinez, L. & Jaworski, D. M. Tissue inhibitor of metalloproteinase-2 promotes neuronal differentiation by acting as an anti-mitogenic signal. J. Neurosci. 25, 4917–4929 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Alfandari, D. et al. Xenopus ADAM 13 is a metalloprotease required for cranial neural crest-cell migration. Curr. Biol. 11, 918–930 (2001).

    CAS  PubMed  Article  Google Scholar 

  59. Vaillant, C. et al. MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum. Mol. Cell. Neurosci. 24, 395–408 (2003).

    CAS  PubMed  Article  Google Scholar 

  60. Ayoub, A. E., Cai, T. Q., Kaplan, R. A. & Luo, J. Developmental expression of matrix metalloproteinases 2 and 9 and their potential role in the histogenesis of the cerebellar cortex. J. Comp. Neurol. 481, 403–415 (2005).

    CAS  PubMed  Article  Google Scholar 

  61. Schlondorff, J. & Blobel, C. P. Metalloprotease-disintegrins: modular proteins capable of promoting cell–cell interactions and triggering signals by protein-ectodomain shedding. J. Cell Sci. 112, 3603–3617 (1999).

    CAS  PubMed  Google Scholar 

  62. Baron, W., Colognato, H. & ffrench-Constant, C. Integrin–growth factor interactions as regulators of oligodendroglial development and function. Glia 49, 467–479 (2005).

    PubMed  Article  Google Scholar 

  63. Xian, C. J. & Zhou, X. F. EGF family of growth factors: essential roles and functional redundancy in the nerve system. Front. Biosci. 9, 85–92 (2004).

    CAS  PubMed  Article  Google Scholar 

  64. Sheffield, J. B., Krasnopolsky, V. & Dehlinger, E. Inhibition of retinal growth cone activity by specific metalloproteinase inhibitors in vitro. Dev. Dyn. 200, 79–88 (1994).

    CAS  PubMed  Article  Google Scholar 

  65. Machida, C. M., Rodland, K. D., Matrisian, L., Magun, B. E. & Ciment, G. NGF induction of the gene encoding the protease transin accompanies neuronal differentiation in PC12 cells. Neuron 2, 1587–1596 (1989).

    CAS  PubMed  Article  Google Scholar 

  66. Nordstrom, L. A., Lochner, J., Yeung, W. & Ciment, G. The metalloproteinase stromelysin-1 (transin) mediates PC12 cell growth cone invasiveness through basal laminae. Mol. Cell. Neurosci. 6, 56–68 (1995).

    CAS  PubMed  Article  Google Scholar 

  67. Hayashita-Kinoh, H. et al. Membrane-type 5 matrix metalloproteinase is expressed in differentiated neurons and regulates axonal growth. Cell Growth Differ. 12, 573–580 (2001).

    CAS  PubMed  Google Scholar 

  68. Sekine-Aizawa, Y. et al. Matrix metalloproteinase (MMP) system in brain: identification and characterization of brain-specific MMP highly expressed in cerebellum. Eur. J. Neurosci. 13, 935–948 (2001).

    CAS  PubMed  Article  Google Scholar 

  69. Weeks, B. S., Nomizu, M., Ramchandran, R. S., Yamada, Y. & Kleinman, H. K. Laminin-1 and the RKRLQVQLSIRT laminin-1 α1 globular domain peptide stimulate matrix metalloproteinase secretion by PC12 cells. Exp. Cell Res. 243, 375–382 (1998).

    CAS  PubMed  Article  Google Scholar 

  70. Fambrough, D., Pan, D., Rubin, G. M. & Goodman, C. S. The cell surface metalloprotease/disintegrin Kuzbanian is required for axonal extension in Drosophila. Proc. Natl Acad. Sci. USA 93, 13233–13238 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. Leighton, P. A. et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410, 174–179 (2001).

    CAS  PubMed  Article  Google Scholar 

  72. Mitchell, K. J. et al. Functional analysis of secreted and transmembrane proteins critical to mouse development. Nature Genet. 28, 241–249 (2001).

    CAS  PubMed  Article  Google Scholar 

  73. Goldsmith, A. P., Gossage, S. J. & ffrench-Constant, C. ADAM23 is a cell-surface glycoprotein expressed by central nervous system neurons. J. Neurosci. Res. 78, 647–658 (2004).

    CAS  PubMed  Article  Google Scholar 

  74. Webber, C. A., Hocking, J. C., Yong, V. W., Stange, C. L. & McFarlane, S. Metalloproteases and guidance of retinal axons in the developing visual system. J. Neurosci. 22, 8091–8100 (2002). The first report to demonstrate that the inhibition of metalloproteinases in vivo affects axonal guidance and growth.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. Hattori, M., Osterfield, M. & Flanagan, J. G. Regulated cleavage of a contact-mediated axon repellent. Science 289, 1360–1365 (2000). Using in vitro systems, the authors showed a role for metalloproteinases in axonal guidance.

    CAS  Article  PubMed  Google Scholar 

  76. Galko, M. J. & Tessier-Lavigne, M. Function of an axonal chemoattractant modulated by metalloprotease activity. Science 289, 1365–1367 (2000).

    CAS  Article  PubMed  Google Scholar 

  77. Schimmelpfeng, K., Gogel, S. & Klambt, C. The function of leak and kuzbanian during growth cone and cell migration. Mech. Dev. 106, 25–36 (2001).

    CAS  PubMed  Article  Google Scholar 

  78. Huang, X., Huang, P., Robinson, M. K., Stern, M. J. & Jin, Y. UNC-71, a disintegrin and metalloprotease (ADAM) protein, regulates motor axon guidance and sex myoblast migration in C. elegans. Development 130, 3147–3161 (2003).

    CAS  PubMed  Article  Google Scholar 

  79. Hehr, C. L., Hocking, J. C. & McFarlane, S. Matrix metalloproteinases are required for retinal ganglion cell axon guidance at select decision points. Development 132, 3371–3379 (2005).

    CAS  PubMed  Article  Google Scholar 

  80. Shubayev, V. I. & Myers, R. R. Matrix metalloproteinase-9 promotes nerve growth factor-induced neurite elongation but not new sprout formation in vitro. J. Neurosci. Res. 77, 229–239 (2004).

    CAS  PubMed  Article  Google Scholar 

  81. Demestre, M. et al. Characterisation of matrix metalloproteinases and the effects of a broad-spectrum inhibitor (BB-1101) in peripheral nerve regeneration. Neuroscience 124, 767–779 (2004).

    CAS  PubMed  Article  Google Scholar 

  82. Ahmed, Z. et al. Matrix metalloproteases: degradation of the inhibitory environment of the transected optic nerve and the scar by regenerating axons. Mol. Cell. Neurosci. 28, 64–78 (2005).

    CAS  PubMed  Article  Google Scholar 

  83. Zuo, J., Neubauer, D., Dyess, K., Ferguson, T. A. & Muir, D. Degradation of chondroitin sulfate proteoglycan enhances the neurite-promoting potential of spinal cord tissue. Exp. Neurol. 154, 654–662 (1998) Introduces the concept that a MMP can be used to remove inhibitory ECM molecules to expose the permissive ones.

    CAS  PubMed  Article  Google Scholar 

  84. Szklarczyk, A., Lapinska, J., Rylski, M., McKay, R. D. & Kaczmarek, L. Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J. Neurosci. 22, 920–930 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. Kim, H. J., Fillmore, H. L., Reeves, T. M. & Phillips, L. L. Elevation of hippocampal MMP-3 expression and activity during trauma-induced synaptogenesis. Exp. Neurol. 192, 60–72 (2005).

    CAS  PubMed  Article  Google Scholar 

  86. Reeves, T. M., Prins, M. L., Zhu, J., Povlishock, J. T. & Phillips, L. L. Matrix metalloproteinase inhibition alters functional and structural correlates of deafferentation-induced sprouting in the dentate gyrus. J. Neurosci. 23, 10182–10189 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. Siebert, H., Dippel, N., Mader, M., Weber, F. & Bruck, W. Matrix metalloproteinase expression and inhibition after sciatic nerve axotomy. J. Neuropathol. Exp. Neurol. 60, 85–93 (2001).

    CAS  PubMed  Article  Google Scholar 

  88. Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002).

    CAS  PubMed  Article  Google Scholar 

  89. Ughrin, Y. M., Chen, Z. J. & Levine, J. M. Multiple regions of the NG2 proteoglycan inhibit neurite growth and induce growth cone collapse. J. Neurosci. 23, 175–186 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Lee, D. H., Strittmatter, S. M. & Sah, D. W. Targeting the Nogo receptor to treat central nervous system injuries. Nature Rev. Drug Discov. 2, 872–878 (2003).

    CAS  Article  Google Scholar 

  91. Weskamp, G. et al. Evidence for a critical role of the tumor necrosis factor α convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR). J. Biol. Chem. 279, 4241–4249 (2004).

    CAS  PubMed  Article  Google Scholar 

  92. Domeniconi, M. et al. MAG induces regulated intramembrane proteolysis of the p75 neurotrophin receptor to inhibit neurite outgrowth. Neuron 46, 849–855 (2005).

    CAS  PubMed  Article  Google Scholar 

  93. Walmsley, A. R. et al. Zinc metalloproteinase-mediated cleavage of the human Nogo-66 receptor. J. Cell Sci. 117, 4591–4602 (2004). Lays the foundation for considering the involvement of metalloproteinases in overcoming inhibition of axonal regrowth by Nogos.

    CAS  PubMed  Article  Google Scholar 

  94. Walmsley, A. R., Mir, A. K. & Frentzel, S. Ectodomain shedding of human Nogo-66 receptor homologue-1 by zinc metalloproteinases. Biochem. Biophys. Res. Commun. 327, 112–116 (2005).

    CAS  PubMed  Article  Google Scholar 

  95. Belien, A. T., Paganetti, P. A. & Schwab, M. E. Membrane-type 1 matrix metalloprotease (MT1-MMP) enables invasive migration of glioma cells in central nervous system white matter. J. Cell Biol. 144, 373–384 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Mannello, F., Luchetti, F., Falcieri, E. & Papa, S. Multiple roles of matrix metalloproteinases during apoptosis. Apoptosis 10, 19–24 (2005) A thorough review of metalloproteinases in life and death decisions of a cell.

    CAS  PubMed  Article  Google Scholar 

  97. Wetzel, M., Rosenberg, G. A. & Cunningham, L. A. Tissue inhibitor of metalloproteinases-3 and matrix metalloproteinase-3 regulate neuronal sensitivity to doxorubicin-induced apoptosis. Eur. J. Neurosci. 18, 1050–1060 (2003).

    CAS  PubMed  Article  Google Scholar 

  98. Naus, S. et al. Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death. J. Biol. Chem. 279, 16083–16090 (2004).

    CAS  PubMed  Article  Google Scholar 

  99. Fowlkes, J. L. & Winkler, M. K. Exploring the interface between metallo-proteinase activity and growth factor and cytokine bioavailability. Cytokine Growth Factor Rev. 13, 277–287 (2002).

    CAS  PubMed  Article  Google Scholar 

  100. Lee, R., Kermani, P., Teng, K. K. & Hempstead, B. L. Regulation of cell survival by secreted proneurotrophins. Science 294, 1945–1948 (2001). Implicates the metalloproteinases in the biology of the neurotrophins.

    CAS  Article  PubMed  Google Scholar 

  101. Hwang, J. J., Park, M. H., Choi, S. Y. & Koh, J. Y. Activation of the Trk signaling pathway by extracellular zinc. Role of metalloproteinases. J. Biol. Chem. 280, 11995–12001 (2005).

    CAS  PubMed  Article  Google Scholar 

  102. Franklin, R. J. Why does remyelination fail in multiple sclerosis? Nature Rev. Neurosci. 3, 705–714 (2002).

    CAS  Article  Google Scholar 

  103. Uhm, J. H., Dooley, N. P., Oh, L. Y. & Yong, V. W. Oligodendrocytes utilize a matrix metalloproteinase, MMP-9, to extend processes along an astrocyte extracellular matrix. Glia 22, 53–63 (1998).

    CAS  PubMed  Article  Google Scholar 

  104. Oh, L. Y. et al. Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes. J. Neurosci. 19, 8464–8475 (1999). One of the first papers to suggest beneficial roles of metalloproteinases in the nervous system.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. Larsen, P. H. & Yong, V. W. The expression of matrix metalloproteinase-12 by oligodendrocytes regulates their maturation and morphological differentiation. J. Neurosci. 24, 7597–7603 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. Sagane, K. et al. Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice. BMC Neurosci. 6, 33 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. Bernstein, H. G. et al. ADAM (a disintegrin and metalloprotease) 12 is expressed in rat and human brain and localized to oligodendrocytes. J. Neurosci. Res. 75, 353–360 (2004).

    CAS  PubMed  Article  Google Scholar 

  108. John, G. R. et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nature Med. 8, 1115–1121 (2002).

    CAS  PubMed  Article  Google Scholar 

  109. Tsai, H. H. et al. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110, 373–383 (2002).

    CAS  Article  PubMed  Google Scholar 

  110. Wang, J. & Tsirka, S. E. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 128, 1622–1633 (2005).

    PubMed  Article  Google Scholar 

  111. Stuve, O. et al. Interferon β-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann. Neurol. 40, 853–863 (1996).

    CAS  PubMed  Article  Google Scholar 

  112. Leppert, D., Waubant, E., Burk, M. R., Oksenberg, J. R. & Hauser, S. L. Interferon β-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann. Neurol. 40, 846–852 (1996).

    CAS  PubMed  Article  Google Scholar 

  113. Yong, V. W. Differential mechanisms of action of interferon-β and glatiramer aetate in MS. Neurology 59, 802–808 (2002).

    CAS  PubMed  Article  Google Scholar 

  114. Yong, V. W. et al. The promise of minocycline in neurology. Lancet Neurol. 3, 744–751 (2004).

    PubMed  Article  Google Scholar 

  115. Overall, C. M. et al. Protease degradomics: mass spectrometry discovery of protease substrates and the CLIP-CHIP, a dedicated DNA microarray of all human proteases and inhibitors. Biol. Chem. 385, 493–504 (2004). Lays the foundation for a key area of future metalloproteinase research, that of identifying substrates of metalloproteinases in particular contexts.

    CAS  PubMed  Article  Google Scholar 

  116. Asahi, M., Sumii, T., Fini, M. E., Itohara, S. & Lo, E. H. Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia. Neuroreport 12, 3003–3007 (2001).

    CAS  PubMed  Article  Google Scholar 

  117. Takahashi, M. et al. In vivo glioma growth requires host-derived matrix metalloproteinase 2 for maintenance of angioarchitecture. Pharmacol. Res. 46, 155–163 (2002).

    CAS  PubMed  Article  Google Scholar 

  118. Dubois, B. et al. Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions. J. Clin. Invest. 104, 1507–1515 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Wang, X. et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J. Neurosci. 20, 7037–7042 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. Asahi, M. et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21, 7724–7732 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Tang, J. et al. Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice. J. Cereb. Blood Flow Metab. 24, 1133–1134 (2004).

    PubMed  Article  CAS  Google Scholar 

  122. Wells, J. E. A., Biernaskie, J., Szymanska, A., Corbett, D. R. & Yong, V. W. Matrix metalloproteinase (MMP)-12 expression has a negative impact on sensorimotor function following intracerebral haemorrhage in mice. Eur. J. Neurosci. 21, 187–196 (2005).

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

The author wishes to thank the numerous trainees who worked on metalloproteinase biology while in the Yong laboratory. A grateful acknowledgement is also due to funding agencies, particularly the Canadian Institutes of Health Research and the Multiple Sclerosis Society of Canada. The author thanks R. Nuttall, A. Fournier and D. Edward for reading through parts of this manuscript, and F. Yong for help with the figures.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

ADAM10

ADAM12

ADAM13

ADAM23

ADAMTS14

kuzbanian

MMP2

MMP3

MMP7

MMP9

MMP14

MMP26

TIMP1

TIMP2

TIMP3

UNC-17

OMIM

multiple sclerosis

Glossary

INTEGRINS

Receptors on cells that interact with ECM proteins or other cell surface molecules, and that regulate important functions such as growth and survival.

ZYMOGEN

An inactive pro-form of an enzyme. All metalloproteinases are initially expressed as zymogens that require processing to expose their active catalytic site.

ECTODOMAIN SHEDDING

Refers to the release of an active factor from the cell membrane, usually from an inactive form, by proteases. For instance, all EGF receptor ligands, which affect development and disease, are released in this manner.

GELATIN ZYMOGRAPHY

A gel-based method, using gels impregnated with gelatin, to measure the level of MMP2 and MMP9 through their ability to degrade gelatin.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

(EAE). An animal model of multiple sclerosis that is initiated in animals by injecting myelin proteins or peptides to raise autoreactive T cells, or by the transfer of autoreactive T cells into naive recipients.

CHEMOKINES

A subfamily of inflammatory molecules that were initially described in regulating the chemotaxis of inflammatory cells, but that also have important roles in other processes, such as cell growth and differentiation.

CHONDROITIN SULPHATE PROTEOGLYCANS

(CSPGs). Important components of the ECM. The deposition of these proteins at sites of CNS injury is an important impediment to axonal regrowth.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yong, V. Metalloproteinases: Mediators of Pathology and Regeneration in the CNS. Nat Rev Neurosci 6, 931–944 (2005). https://doi.org/10.1038/nrn1807

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1807

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing