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Cited by 206Protease and Inhibitor MechanismsTraumatic Brain Injury and Neurovascular DisturbancesNeuroinflammation and Neurodegeneration Mechanisms

Matrix metalloproteases and their inhibitors are produced by overlapping populations of activated astrocytes

Muir, E.M, Adcock, K.H, Morgenstern, D.A, Clayton, R, von Stillfried, N, Rhodes, K, Ellis, C, Fawcett, J.W +1 more·2002·Molecular Brain Research
DOI 10.1016/s0169-328x(02)00132-8
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Abstract

Matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteases (TIMPs) are involved in many cell migration phenomena and produced by many cell types, including neurons and glia. To assess their possible roles in brain injury and regeneration, we investigate their production by glial cells, after brain injury and in tissue culture, and we investigate whether they are capable of digesting known axon-inhibitory proteoglycans. To determine the action of MMPs, we incubated astrocyte conditioned medium with activated MMPs, then did western blots for several chondroitin sulphate proteoglycans. MMP-3 digested all five proteoglycans tested, whereas MMP-2 digested only two and MMP-9 none. To determine whether MMPs or TIMPs are produced by astrocytes in vitro, we tested both primary cultures and astrocyte cell lines by western blotting, and compared them with Schwann cells. All cultures produced at least some MMPs and TIMPs, with no obvious correlation with the ability of axons to grow on those cells. Both MMP-9 and TIMP-3 were regulated by various cytokines. To determine which cells produce MMPs and TIMPs after brain injury, we made lesions of adult rat cortex, and did immunohistochemistry. MMP-2 was seen to be induced in activated astrocytes through the whole thickness of the cortex but not deeper, but MMP-3 was not seen in the injured brain. TIMP-2 and TIMP-3 immunoreactivities were induced in activated astrocytes in deep cortex and the underlying white matter. In situ hybridisation confirmed induction of TIMP-2 in glia as well as neurons, but showed no expression of TIMP-4. These results show that both MMPs and TIMPs are produced by some astrocytes, but TIMP production is particularly strong, especially in deep cortex and white matter which is more inhibitory for axon regeneration. Conversely the MMPs produced may not be adequate to promote migration of cells and axons within the glial scar.

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Authors
Muir, E. M., Adcock, K. H., Morgenstern, D. A., Clayton, R., von Stillfried, N., Rhodes, K., Ellis, C., Fawcett, J. W., & Rogers, J. H.
Affiliations
University of Cambridge (GB)
Corresponding author
Rogers, J.H
ORCID
Venue
Molecular Brain Research
Publisher
Elsevier BV
Published
2002-04
Volume
100
Issue
1-2
Pages
103-117
ISSN
0169-328X (ISSN-L)
DOI
10.1016/s0169-328x(02)00132-8
OpenAlex
W2057974205
Cited by
206
References
98
Citations by year
2026: 4 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 8 · 2020: 10 · 2019: 5 · 2018: 6 · 2017: 2 · 2016: 2 · 2015: 9 · 2014: 10 · 2013: 7 · 2012: 7
FWCI
4.24
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Molecular Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
matrix metalloproteinases, tissue inhibitors of metalloproteinases, brain injury, axon regeneration, chondroitin sulfate proteoglycans, MMP-2, MMP-3, MMP-9, TIMP-2, TIMP-3, glial scar, Schwann cells, cytokine regulation, white matter, cortical lesions
MeSH terms
Tissue Inhibitor of Metalloproteinase-4, Animals, Animals, Newborn, Antibody Specificity, Astrocytes, Brain, Brain Injuries, Cells, Cultured, Cerebral Cortex, Gliosis, Nerve Regeneration, Chondroitin Sulfate Proteoglycans, RNA, Messenger, Up-Regulation, Cytokines, In Situ Hybridization, Matrix Metalloproteinase 3, Tissue Inhibitor of Metalloproteinases, Tissue Inhibitor of Metalloproteinase-2, Tissue Inhibitor of Metalloproteinase-3, Growth Cones, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Rats

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