An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice.
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.
Wells
Jennifer E A
JE
Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Rice
Tiffany K
TK
Nuttall
Robert K
RK
Edwards
Dylan R
DR
Zekki
Hakima
H
Rivest
Serge
S
Yong
V Wee
VW
D000818:Animals; D002199:Capillary Permeability / Q000235:genetics; D002452:Cell Count; D019070:Cell Lineage; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D006614:Hindlimb / Q000503:physiopathology; D017403:In Situ Hybridization; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008297:Male; D053508:Matrix Metalloproteinase 12; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation
D012333:RNA, Messenger; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12