Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury.
Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in both injury and repair mechanisms in the CNS. Pharmacological blockade of MMPs, limited to the first several days after spinal cord injury, improves locomotor recovery. This beneficial response is, however, lost when treatment is extended beyond the acutely injured cord to include wound healing and tissue remodeling. This suggests that some MMPs play a beneficial role in wound healing. To test this hypothesis, we investigated the role of MMP-2, which is actively expressed during wound healing, in white matter sparing and axonal plasticity, the formation of a glial scar, and locomotor recovery after spinal cord injury. MMP-2 increased between 7 and 14 d after injury, where it was immunolocalized in reactive astrocytes bordering the lesion epicenter. There was reduced white matter sparing and fewer serotonergic fibers, caudal to the lesion in injured MMP-2 null animals. MMP-2 deficiency also resulted in increased immunoreactivity to chondroitin sulfate proteoglycans and a more extensive astrocytic scar. Most importantly, locomotion in an open field, performance on a rotarod, and grid walking were significantly impaired in injured MMP-2 null mice. Our findings suggest that MMP-2 promotes functional recovery after injury by regulating the formation of a glial scar and white matter sparing and/or axonal plasticity. Thus, strategies exploiting MMPs as therapeutic targets must balance these beneficial effects during wound healing with their adverse interactions in the acutely injured spinal cord.
Hsu
Jung-Yu C
JY
Department of Neurological Surgery, University of California, San Francisco, California 94143, USA. jung-yu.hsu@ucsf.edu
McKeon
Robert
R
Goussev
Staci
S
Werb
Zena
Z
Lee
Jung-Uek
JU
Trivedi
Alpa
A
Noble-Haeusslein
Linda J
LJ
D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000473:pathology; D015415:Biomarkers; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis; D002921:Cicatrix / Q000201:enzymology* / Q000209:etiology; D003288:Contusions / Q000201:enzymology / Q000503:physiopathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005911:Gliosis / Q000201:enzymology* / Q000209:etiology; D007796:Laminectomy; D008124:Locomotion / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009186:Myelin Sheath / Q000502:physiology; D009473:Neuronal Plasticity; D020127:Recovery of Function; D012701:Serotonin / Q000032:analysis; D013116:Spinal Cord / Q000737:chemistry / Q000473:pathology; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology*
D015415:Biomarkers; D011508:Chondroitin Sulfate Proteoglycans; D005904:Glial Fibrillary Acidic Protein; D053773:Transforming Growth Factor beta1; D012701:Serotonin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9