Abstract
Matrix metalloproteinase-1 (MMP-1), a member of the matrix metalloproteinases family, plays an integral role in extracellular matrix degradation and has been reportedly involved in the regulation of the brain or spinal cord traumatic neurovascular remodeling. Although the critical involvement of MMP-1 in the metastasis of tumors has been extensively documented, the role of MMP-1 in the pathology of neurological diseases remains largely elusive. In the present study, we established an adult rat spinal cord injury (SCI) model and investigated a potential role of MMP-1 in the pathological process of SCI. Using Western blot analysis, we identified notable expression change of MMP-1 after SCI. Immunohistochemistry showed that MMP-1 was distributed widely in rat spinal cord. Double immunofluorescence staining revealed that MMP-1 immunoreactivity was predominantly increased in neurons and astrocytes following SCI. Moreover, after injury, colocalization of MMP-1/active caspase-3 in neurons (NeuN-positive), and colocalization of MMP-1/PCNA in astrocytes (GFAP-positive) were clearly observed. We also examined the protein expression of PCNA, active caspase-3, Bcl-2, and Bax and found that the expression of the proteins was closely correlated with that of MMP-1. Taken together, our findings indicate that MMP-1 might play an important role in the regulation of neuronal apoptosis and astrocyte proliferation after SCI.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Agapova OA, Kaufman PL, Lucarelli MJ, Gabelt BT, Hernandez MR (2003) Differential expression of matrix metalloproteinases in monkey eyes with experimental glaucoma or optic nerve transection. Brain Res 967:132–143
Agarwal A et al (2008) Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer. Mol Cancer Ther 7:2746–2757. doi:10.1158/1535-7163.MCT-08-0177
Agarwal A, Tressel SL, Kaimal R, Balla M, Lam FH, Covic L, Kuliopulos A (2010) Identification of a metalloprotease-chemokine signaling system in the ovarian cancer microenvironment: implications for antiangiogenic therapy. Cancer Res 70:5880–5890. doi:10.1158/0008-5472.CAN-09-4341
Bao Y et al (2012) CD36 is involved in astrocyte activation and astroglial scar formation. J Cereb Blood Flow Metab 32:1567–1577. doi:10.1038/jcbfm.2012.52
Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats Journal of neurotrauma 12:1–21
Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A (2005) PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120:303–313. doi:10.1016/j.cell.2004.12.018
Bujor AM, Pannu J, Bu S, Smith EA, Muise-Helmericks RC, Trojanowska M (2008) Akt blockade downregulates collagen and upregulates MMP1 in human dermal fibroblasts. J Invest Dermatol 128:1906–1914. doi:10.1038/jid.2008.39
Buss A, Pech K, Kakulas BA, Martin D, Schoenen J, Noth J, Brook GA (2007) Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury. BMC Neurol 7:17. doi:10.1186/1471-2377-7-17
Casha S, Yu WR, Fehlings MG (2005) FAS deficiency reduces apoptosis, spares axons and improves function after spinal cord injury. Exp Neurol 196:390–400. doi:10.1016/j.expneurol.2005.08.020
Chen DF, Schneider GE, Martinou JC, Tonegawa S (1997) Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature 385:434–439. doi:10.1038/385434a0
Chen J et al (2013) MCM7 expression is altered in rat after spinal cord injury. J Mol Neurosci 51:82–91. doi:10.1007/s12031-013-0003-y
Choi DC, Lee JY, Moon YJ, Kim SW, Oh TH, Yune TY (2010) Acupuncture-mediated inhibition of inflammation facilitates significant functional recovery after spinal cord injury. Neurobiol Dis 39:272–282. doi:10.1016/j.nbd.2010.04.003
Dang AB, Tay BK, Kim HT, Nauth A, Alfonso-Jaume MA, Lovett DH (2008) Inhibition of MMP2/MMP9 after spinal cord trauma reduces apoptosis. Spine 33:E576–579. doi:10.1097/BRS.0b013e31817ecc87
Ducker TB, Kindt GW, Kempf LG (1971) Pathological findings in acute experimental spinal cord trauma. J Neurosurg 35:700–708. doi:10.3171/jns.1971.35.6.0700
Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ, Boulos PT, Ellegala DB, Dumont AS (2001) Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 24:254–264
Fairholm D, Turnbull I (1970) Microangiographic study of experimental spinal injuries in dogs and rabbits. Surg forum 21:453–455
Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49:377–391
Feng L, Balakir R, Precht P, Horton WE Jr (1999) Bcl-2 regulates chondrocyte morphology and aggrecan gene expression independent of caspase activation and full apoptosis. J Cell Biochem 74:576–586
Goldberg GI, Wilhelm SM, Kronberger A, Bauer EA, Grant GA, Eisen AZ (1986) Human fibroblast collagenase. Complete primary structure and homology to an oncogene transformation-induced rat protein. J Biol Chem 261:6600–6605
Gross J, Lapiere CM (1962) Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA 48:1014–1022
Gruner JA (1992) A monitored contusion model of spinal cord injury in the rat. J Neurotrauma 9:123–126; discussion 126–128
Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY, Lipton SA (2005) A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 25:6401–6408. doi:10.1523/JNEUROSCI.1563-05.2005
Hang Q et al (2014) Asparagine-linked glycosylation of bone morphogenetic protein-2 is required for secretion and osteoblast differentiation. Glycobiology 24:292–304. doi:10.1093/glycob/cwt110
Hermann GE, Rogers RC, Bresnahan JC, Beattie MS (2001) Tumor necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord. Neurobiol Dis 8:590–599. doi:10.1006/nbdi.2001.0414
Jana A, Hogan EL, Pahan K (2009) Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death. J Neurol Sci 278:5–15. doi:10.1016/j.jns.2008.12.010
Kahari VM, Saarialho-Kere U (1997) Matrix metalloproteinases in skin. Exp Dermatol 6:199–213
Khalatbary AR, Zarrinjoei GR (2012) Anti-inflammatory effect of oleuropein in experimental rat spinal cord trauma. Iran Red Crescent Med J 14:229–234
Kiaei M et al (2007) Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol 205:74–81. doi:10.1016/j.expneurol.2007.01.036
Kunapuli P, Kasyapa CS, Hawthorn L, Cowell JK (2004) LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway. J Biol Chem 279:23151–23157. doi:10.1074/jbc.M314192200
Lee SR, Tsuji K, Lo EH (2004) Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci 24:671–678. doi:10.1523/JNEUROSCI.4243-03.2004
Liu Y, Figley S, Spratt SK, Lee G, Ando D, Surosky R, Fehlings MG (2010) An engineered transcription factor which activates VEGF-A enhances recovery after spinal cord injury. Neurobiol Dis 37:384–393. doi:10.1016/j.nbd.2009.10.018
Lopez-Vales R et al (2010) Fenretinide promotes functional recovery and tissue protection after spinal cord contusion injury in mice. J Neurosci 30:3220–3226. doi:10.1523/JNEUROSCI.5770-09.2010
Lu P, Takai K, Weaver VM, Werb Z (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3:a005058. doi:10.1101/cshperspect.a005058
Marani M, Tenev T, Hancock D, Downward J, Lemoine NR (2002) Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol 22:3577–3589
Marriott JB et al (2003) A novel subclass of thalidomide analogue with anti-solid tumor activity in which caspase-dependent apoptosis is associated with altered expression of bcl-2 family proteins. Cancer Res 63:593–599
Martinou JC, Youle RJ (2011) Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell 21:92–101. doi:10.1016/j.devcel.2011.06.017
McCawley LJ, Matrisian LM (2000) Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6:149–156
Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573. doi:10.1016/j.cardiores.2005.12.002
Nguyen N, Kuliopulos A, Graham RA, Covic L (2006) Tumor-derived Cyr61(CCN1) promotes stromal matrix metalloproteinase-1 production and protease-activated receptor 1-dependent migration of breast cancer cells. Cancer Res 66:2658–2665. doi:10.1158/0008-5472.CAN-05-2082
Noel A et al (2012) New and paradoxical roles of matrix metalloproteinases in the tumor microenvironment Frontiers in pharmacology 3:140. doi:10.3389/fphar.2012.00140
Ola MS, Nawaz M, Ahsan H (2011) Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem 351:41–58. doi:10.1007/s11010-010-0709-x
Pallavi SK, Ho DM, Hicks C, Miele L, Artavanis-Tsakonas S (2012) Notch and Mef2 synergize to promote proliferation and metastasis through JNK signal activation in Drosophila. EMBO J 31:2895–2907. doi:10.1038/emboj.2012.129
Popovich PG, Guan Z, McGaughy V, Fisher L, Hickey WF, Basso DM (2002) The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol 61:623–633
Raghupathi R (2004) Cell death mechanisms following traumatic brain injury. Brain Pathol 14:215–222
Rahman MA, Kim NH, Yang H, Huh SO (2012) Angelicin induces apoptosis through intrinsic caspase-dependent pathway in human SH-SY5Y neuroblastoma cells. Mol Cell Biochem 369:95–104. doi:10.1007/s11010-012-1372-1
Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29:1020–1030
Rosell A, Lo EH (2008) Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol 8:82–89. doi:10.1016/j.coph.2007.12.001
Rosenberg GA (2002) Matrix metalloproteinases in neuroinflammation. Glia 39:279–291. doi:10.1002/glia.10108
Ryu B et al (2011) Global analysis of BRAFV600E target genes in human melanocytes identifies matrix metalloproteinase-1 as a critical mediator of melanoma growth. J Invest Dermatol 131:1579–1583. doi:10.1038/jid.2011.65
Saadoun S, Bell BA, Verkman AS, Papadopoulos MC (2008) Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice. Brain 131:1087–1098. doi:10.1093/brain/awn014
Senter HJ, Venes JL (1978) Altered blood flow and secondary injury in experimental spinal cord trauma. J Neurosurg 49:569–578. doi:10.3171/jns.1978.49.4.0569
Shang L, Qin J, Chen LB, Liu BX, Jacques M, Wang H (2009) Effects of sodium ferulate on human osteoarthritic chondrocytes and osteoarthritis in rats. Clin Exp Pharmacol Physiol 36:912–918. doi:10.1111/j.1440-1681.2009.05171.x
Soell M, Elkaim R, Tenenbaum H (2002) Cathepsin C, matrix metalloproteinases, and their tissue inhibitors in gingiva and gingival crevicular fluid from periodontitis-affected patients. J Dent Res 81:174–178
Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Ann Rev Cell Dev Biol 17:463–516. doi:10.1146/annurev.cellbio.17.1.463
Sunkaria A, Wani WY, Sharma DR, Gill KD (2012) Dichlorvos exposure results in activation induced apoptotic cell death in primary rat microglia. Chem Res Toxicol 25:1762–1770. doi:10.1021/tx300234n
Tang MJ, Tai IT (2007) A novel interaction between procaspase 8 and SPARC enhances apoptosis and potentiates chemotherapy sensitivity in colorectal cancers. J Biol Chem 282:34457–34467. doi:10.1074/jbc.M704459200
Trivedi V et al (2009) Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell 137:332–343. doi:10.1016/j.cell.2009.02.018
Uhlirova M, Bohmann D (2006) JNK- and Fos-regulated Mmp1 expression cooperates with Ras to induce invasive tumors in Drosophila. EMBO J 25:5294–5304. doi:10.1038/sj.emboj.7601401
Ullah N, Naseer MI, Ullah I, Lee HY, Koh PO, Kim MO (2011) Protective effect of pyruvate against ethanol-induced apoptotic neurodegeneration in the developing rat brain. Neuropharmacology 61:1248–1255. doi:10.1016/j.neuropharm.2011.06.031
Vos CM, Sjulson L, Nath A, McArthur JC, Pardo CA, Rothstein J, Conant K (2000) Cytotoxicity by matrix metalloprotease-1 in organotypic spinal cord and dissociated neuronal cultures. Exp Neurol 163:324–330. doi:10.1006/exnr.2000.7388
Vu TH, Werb Z (2000) Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 14:2123–2133
Wang X et al (2000) Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci 20:7037–7042
Woessner JF Jr (1998) Role of matrix proteases in processing enamel proteins Connective tissue research 39:69–73; discussion 141–149
Wu J, Pajoohesh-Ganji A, Stoica BA, Dinizo M, Guanciale K, Faden AI (2012) Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion. J Neuroinflamm 9:169. doi:10.1186/1742-2094-9-169
Xiao XY, Wang XD, Zang DY (2012) MMP1-1607 1G/2G polymorphism and lung cancer risk: a meta-analysis. Tumour Biol 33:2385–2392. doi:10.1007/s13277-012-0502-4
Xu D et al (2011) Overexpression of glucose-regulated protein 94 after spinal cord injury in rats. J Neurol Sci 309:141–147. doi:10.1016/j.jns.2011.06.024
Yang E et al (2009) Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. Cancer Res 69:6223–6231. doi:10.1158/0008-5472.CAN-09-0187
Yin X et al (2012) Tanshinone IIA attenuates the inflammatory response and apoptosis after traumatic injury of the spinal cord in adult rats. PLoS ONE 7:e38381. doi:10.1371/journal.pone.0038381
Yong VW (2005) Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 6:931–944. doi:10.1038/nrn1807
Young W (1993) Secondary injury mechanisms in acute spinal cord injury. J Emerg Med 11(Suppl 1):13–22
Zhang J et al (2013) Expression of RBMX after spinal cord injury in rats. J Mol Neurosci 49:417–429. doi:10.1007/s12031-012-9914-2
Zhao BQ et al (2006) Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12:441–445. doi:10.1038/nm1387
Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110
Acknowledgments
This work was supported by National Basic Research Program of China (973 Program, No.2012CB822104); National Natural Science Foundation of China (31170766); Key Project Natural Science Foundation of Jiangsu University and College (No.11KJA310002); Nantong City Social Development Projects funds (HS2012032); A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Ying Zhou and Zhiming Cui have contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
10571_2014_90_MOESM1_ESM.tif
Immunohistochemical analysis of Myelin Basic Protein (MBP) distribution in adult rat spinal cord after SCI; The distribution of MBP in adult rat spinal cord was detected by immunohistochemical. Low-power views of cross-sections immunostained with antibody specific for MBP in sham spinal cord (a) and 5 days after injury (b). Higher-power views in the gray matter (c, d), dorsal horn (i, j), ventral (g, h) and nonspecific region (e, f) in the white matter of the spinal cord. Error bars represent SEM. Scale bars 200 μm (a, b), 20 μm (c, d) and 100 μm (e–j) (TIFF 11581 kb)
Rights and permissions
About this article
Cite this article
Zhou, Y., Cui, Z., Xia, X. et al. Matrix Metalloproteinase-1 (MMP-1) Expression in Rat Spinal Cord Injury Model. Cell Mol Neurobiol 34, 1151–1163 (2014). https://doi.org/10.1007/s10571-014-0090-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-014-0090-5