An Adverse Role for Matrix Metalloproteinase 12 after Spinal Cord Injury in Mice

Abstract

We investigated the role of matrix metalloproteinases (MMPs) in acute spinal cord injury (SCI). Transcripts encoding 22 of the 23 known mammalian MMPs were measured in the mouse spinal cord at various time points after injury. Although there were significant changes in the expression levels of multiple MMPs, MMP-12 was increased 189-fold over normal levels, the highest of all MMPs examined. To evaluate the role of MMP-12 in SCI, spinal cord compression was performed in wild-type (WT) and MMP-12 null mice. Behavioral analyses were conducted for 4 weeks using the Basso-Beattie-Bresnahan (BBB) locomotor rating scale as well as the inclined plane test. The results show that MMP-12 null mice exhibited significantly improved functional recovery compared with WT controls. Twenty-eight days after injury, the BBB score in the MMP-12 group was 7, representing extensive movement of all three hindlimb joints, compared with 4 in the WT group, representing only slight movement of these joints. Furthermore, MMP-12 null mice showed recovery of hindlimb strength more rapidly than control mice, with significantly higher inclined plane scores on days 14 and 21 after SCI. Mechanistically, there was decreased permeability of the blood-spinal barrier and reduced microglial and macrophage density in MMP-12 null mice compared with WT controls. This is the first study to profile the expression patterns of a majority of the known MMPs after spinal cord compression. The data indicate that MMP-12 expression after spinal cord trauma is deleterious and contributes to the development of secondary injury in SCI.

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

“…It was known that a larger amount of neuropsin, a serine protease, was found to be located in oligodendrocytes, and neuropsin-deficient mice showed alleviation of the severity of apoptosis of the oligodendrocytes (94). In addition to neuropsin, other serine proteases such as tissue-type plasminogen activator and matrix metalloproteinases also play a detrimental role in the pathology after CNS injury (95,96). In fact, serpins, known as the serine protease inhibitor protein family, play a key role in regulating the activity of serine proteases in vivo (97).…”

Sorting of growth plate chondrocytes allows the isolation and characterization of cells of a defined differentiation status

“…Gene-specific primers and prevalidated probes of the Roche Universal Probe Library were used for Gdf10, osteomodulin, Spp1, Col10a1, Runx2, Ihh, and Sox9, whereas a preexisting primer-probe pair was employed for Mmp10 and Mmp13. (28) qPCR reactions were performed using the qPCR SuperMix-UDG Kit (Invitrogen) on the DNAengine-Opticon2 System (Bio-Rad, Hercules, CA). For each primer-probe pair, the efficiency was determined and the relative expression levels were calculated using the DDC T method.…”

Membrane-type Matrix Metalloproteinase-3 Regulates Neuronal Responsiveness to Myelin through Nogo-66 Receptor 1 Cleavage

“…Furthermore, MT-MMP mRNA levels in total tissue and microglia are regulated in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis (30). Several MMP transcripts are regulated in the spinal cord following a clip compression injury (31). Although MT-MMP transcripts are not regulated in this paradigm, it is possible that their proteolytic activity is affected by processing of pro-MT-MMPs to mature forms.…”

“…Its expression also increases when P19 cells are differentiated into neurons (43). Intriguingly, MT3-MMP expression decreases following induction of experimental autoimmune encephalomyelitis or traumatic injury in the entorhinal cortex and spinal cord (30,31), and this differs from the elevated expression of several other MMPs. The role of MT3-MMP in regulating NgR1-dependent effects on nerve repair, synaptic plasticity, and additional CNS functions remains to be explored.…”