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Published on: April 5, 2016
Inhibition of MMP2/MMP9 after spinal cord trauma reduces apoptosis
Alexis B C Dang1, Bobby K-B Tay, Hubert T Kim
1Division of Orthopaedic Surgery, Veterans Affairs Medical Center, San Francisco, CA, USA.
Study Design:
Randomized controlled trial.
Objective:
To characterize the increase in gelatinase A (MMP2) activity after spinal cord injury (SCI) in the mouse model, and the effects of MMP2/MMP9 inhibition on apoptotic cells.
Summary Of Background Data:
Clinical consequences of SCI are due to a series of secondary injury cascades. Matrix metalloproteinases are thought play a key role in this, leading to apoptotic cell death.
Methods:
SCI via a drop tower in mice was used. MMP2 beta-gal reporter mice were used to quantify the level of MMP2 after SCI. In a follow-up experiment, mice which underwent SCI were randomized to daily SQ injections of MMP2/MMP9 inhibitor versus placebo. MMP2 levels were quantified and histology was performed with TUNEL and Luxol fast blue staining.
Results:
MMP2 transcription was significantly upregulated after SCI, by the beta-gal assay. Inhibition of MMP2/MMP9 activity after SCI led to statistically significant decreases in apoptosis within the zone of injury. There was a trend towards preservation of myelin by preserved luxol fast blue staining.
Conclusion:
After SCI, MMP2 is upregulated along with neuron and glial cells apoptosis. The level of apoptosis could be reduced with MMP2/MMP9 inhibition. This supports MMP2 as cause for apoptosis after SCI with the potential for therapeutic intervention as apoptosis can be reduced with MMP2 inhibition.
Insights
Matrix metalloproteinase-2 (MMP2) activity increases after spinal cord injury (SCI), leading to cell death. Inhibiting MMP2/MMP9 reduced apoptosis, suggesting therapeutic potential for SCI.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Spinal cord injury (SCI) triggers secondary injury cascades.
- Matrix metalloproteinases (MMPs) are implicated in SCI pathogenesis.
- MMPs contribute to apoptotic cell death following SCI.
Purpose of the Study:
- To characterize gelatinase A (MMP2) activity post-SCI in a mouse model.
- To investigate the effects of MMP2/MMP9 inhibition on apoptotic cells after SCI.
Main Methods:
- SCI induced using a drop tower in mice.
- MMP2 expression quantified using MMP2 beta-gal reporter mice.
- Randomized trial of MMP2/MMP9 inhibitor versus placebo post-SCI.
- Histological analysis included TUNEL and Luxol fast blue staining.
Main Results:
- MMP2 transcription significantly upregulated post-SCI.
- MMP2/MMP9 inhibition markedly decreased apoptosis in the injury zone.
- A trend towards preserved myelin was observed with MMP2/MMP9 inhibition.
Conclusions:
- MMP2 upregulation correlates with neuronal and glial apoptosis after SCI.
- MMP2/MMP9 inhibition effectively reduces apoptosis post-SCI.
- MMP2 inhibition presents a potential therapeutic strategy for SCI.
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