title: Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord.
abstract: In the injured spinal cord, a glial scar forms and becomes a major obstacle to axonal regeneration. Formation of the glial scar involves migration of astrocytes toward the lesion. Matrix metalloproteinases (MMPs), including MMP-9 and MMP-2, govern cell migration through their ability to degrade constituents of the extracellular matrix. Although MMP-9 is expressed in reactive astrocytes, its involvement in astrocyte migration and formation of a glial scar is unknown. Here we found that spinal cord injured, wild-type mice expressing MMPs developed a more severe glial scar and enhanced expression of chondroitin sulfate proteoglycans, indicative of a more inhibitory environment for axonal regeneration/plasticity, than MMP-9 null mice. To determine whether MMP-9 mediates astrocyte migration, we conducted a scratch wound assay using astrocytes cultured from MMP-9 null, MMP-2 null, and wild-type mice. Gelatin zymography confirmed the expression of MMP-9 and MMP-2 in wild-type cultures. MMP-9 null astrocytes and wild-type astrocytes, treated with an MMP-9 inhibitor, exhibited impaired migration relative to untreated wild-type controls. MMP-9 null astrocytes showed abnormalities in the actin cytoskeletal organization and function but no detectable untoward effects on proliferation, cellular viability, or adhesion. Interestingly, MMP-2 null astrocytes showed increased migration, which could be attenuated in the presence of an MMP-9 inhibitor. Collectively, our studies provide explicit evidence that MMP-9 is integral to the formation of an inhibitory glial scar and cytoskeleton-mediated astrocyte migration. MMP-9 may thus be a promising therapeutic target to reduce glial scarring during wound healing after spinal cord injury.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, California 94143, USA. jungyu.hsu@gmail.com
authors.forename: Jung-Yu C
authors.initials: JY
authors.lastname: Hsu
authors.forename: Lilly Y W
authors.initials: LY
authors.lastname: Bourguignon
authors.forename: Christen M
authors.initials: CM
authors.lastname: Adams
authors.forename: Karine
authors.initials: K
authors.lastname: Peyrollier
authors.forename: Haoqian
authors.initials: H
authors.lastname: Zhang
authors.forename: Thomas
authors.initials: T
authors.lastname: Fandel
authors.forename: Christine L
authors.initials: CL
authors.lastname: Cun
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Noble-Haeusslein
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000201:enzymology / Q000473:pathology*
chemical_list: D000199:Actins; D011508:Chondroitin Sulfate Proteoglycans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9