title: Matrix metalloproteinase-3 promotes early blood-spinal cord barrier disruption and hemorrhage and impairs long-term neurological recovery after spinal cord injury.
abstract: After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption by matrix metalloproteinases (MMPs) leads to BSCB permeability and blood cell infiltration, contributing to permanent neurological disability. Herein, we report that MMP-3 plays a critical role in BSCB disruption after SCI in mice. MMP-3 was induced in infiltrated neutrophils and blood vessels after SCI, and NF-κB as a transcription factor was involved in MMP-3 expression. BSCB permeability and blood cell infiltration after injury were more reduced in Mmp3 knockout (KO) mice than in wild-type (WT) mice, which was significantly inhibited by Mmp3 siRNA or a general inhibitor of MMPs, N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid. The level of tight junction proteins, such as occludin and zonula occludens-1, which decreased after SCI, was also higher in Mmp3 KO than in WT mice. Exogenously, MMP-3 injection into the normal spinal cord also induced BSCB permeability. Furthermore, MMP-9 activation after injury was mediated by MMP-3 activation. Finally, improved functional recovery was observed in Mmp3 KO mice compared with WT mice after injury. These results demonstrated the role of MMP-3 in BSCB disruption after SCI for the first time and suggest that the regulation of MMP-3 can be considered a therapeutic target to inhibit BSCB disruption and hemorrhage, and thereby enhance functional recovery after acute SCI.
authors.affiliation: Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Jee Youn
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Choi
authors.affiliation: Department of Microbiology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Ahn
authors.affiliation: Department of Life Science, Sogang University, Seoul, Republic of Korea.
authors.forename: Bong Gun
authors.initials: BG
authors.lastname: Ju
authors.affiliation: Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea. Electronic address: tyune@khu.ac.kr.
authors.forename: Tae Young
authors.initials: TY
authors.lastname: Yune
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000378:metabolism*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D019278:Matrix Metalloproteinase 3