MMP-Related Gelatinase Activity Is Strongly Induced in Scar Tissue of Injured Adult Spinal Cord and Forms Pathways for Ingrowing Neurites

Duchossoy, Yann; Horvat, Jean-Claude; Stettler, Olivier

doi:10.1006/mcne.2001.0986

Cited by 93 publications

(85 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…36 Although it is possible that other members of the MMP family may be involved in early tissue injury and wound healing in the injured spinal cord, we have focused on the roles of MMP-9 and -2 because of their established links to early barrier disruption, inflammation, angiogenesis, and glial scar formation. 9,27,36 Excessive activity of MMPs can be detrimental, leading to pathological conditions including barrier disruption, inflammation, and demyelination. 46 These proteases, however, are also integral to wound healing associated with angiogenesis.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing

Goussev¹,

Hsu²,

Lin³

et al. 2003

Journal of Neurosurgery: Spine

View full text Add to dashboard Cite

Object. Matrix metalloproteinases (MMPs), particularly MMP-9/gelatinase B, promote early inflammation and barrier disruption after spinal cord injury (SCI). Early blockade of MMPs after injury provides neuroprotection and improves motor outcome. There is recent evidence, however, that MMP-9 and MMP-2/gelatinase A participate in later wound healing in the injured cord. The authors therefore examined the activity of these gelatinases during revascularization and glial scar formation in the contused murine spinal cord. Methods. Gelatinase activity was evaluated using gelatin zymography 24 hours after a mild, moderate, or severe contusion injury. The active form of MMP-2 was not detected, whereas MMP-9 activity was evident in all SCI groups and rose with increasing injury severity. The temporal expression of gelatinases was then examined using gelatin zymography after a moderate SCI. The active form of MMP-9 was most prominent at 1 day, extended through the early period of revascularization, and returned to control by 14 days. The active form of MMP-2 appeared at 7 days postinjury and remained elevated compared with that documented in sham-treated mice for at least 21 days. Increased MMP-2 activity coincided with both revascularization and glial scar formation. Using in situ zymography, gelatinolytic activity was detected in the meninges, vascular elements, glia, and macrophage-like cells in the injured cord. Results of immunolabeling confirmed the presence of gelatinase in vessels during revascularization and in reactive astrocytes associated with glial scar formation. Conclusions. These findings suggest that although MMP-9 and -2 exhibit overlapping expression during revascularization, the former is associated with acute injury responses and the latter with formation of a glial scar.

show abstract

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing

Goussev¹,

Hsu²,

Lin³

et al. 2003

Journal of Neurosurgery: Spine

View full text Add to dashboard Cite

show abstract

“…MMPs also assume beneficial, specialized roles that include regulating axonal growth and guidance during development as well as promoting axonal regeneration and synaptic plasticity in the CNS (Duchossoy et al, 2001;Yong, 2005;Zhao et al, 2006). It is likely that they participate in wound healing based, in part, on their ability to degrade the ECM and release cryptic ECM molecules that regulate angiogenesis (Chang and Werb, 2001).…”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

Hsu¹,

McKeon²,

Goussev³

et al. 2006

J. Neurosci.

205

184

View full text Add to dashboard Cite

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.

show abstract

Section: Rationale For Studying the Role Of Proteoglycans In Cns Injumentioning

confidence: 99%

“…Stettler et al provided evidence that matrix metalloproteinases that normally digest CSPGs in peripheral nervous system injuries are also present in the CNS, and that laminin and CSPG expression are both upregulated at the site of CNS injuries [24]. In a separate study, hyaluronidase treatment of adult spinal cord injuries (SCI) regions also helped remove CSPGs from the wound site.…”

Section: Rationale For Studying the Role Of Proteoglycans In Cns Injumentioning

confidence: 99%

“…Davies et al found that chondroitin sulfate proteoglycans (CSPG) are a major constituent of the glial scar and that dorsal root ganglion (DRG) outgrowth termination coincided with an increase in CSPG expression density [21]. Other sources have also shown that CSPGs are upregulated after CNS injuries [22][23][24][25].Interestingly, native adult CNS neurons actually posses the intrinsic ability to regenerate when the wound healing environment is prepared by eliminating inhibitory factors [23,26,27]. In addition to CSPGs, inhibitory molecules such as myelin-associated glycoprotein (MAG) found in myelin debris have been shown to inhibit neuron regeneration and cause growth cone collapse upon contact.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The effects of proteoglycan surface patterning on neuronal pathfinding

Hlady

Hodgkinson

2007

Materialwissenschaft Werkst

View full text Add to dashboard Cite

Protein micropatterning techniques are increasingly applied in cell choice assays to investigate fundamental biological phenomena that contribute to the host response to implanted biomaterials, and to explore the effects of protein stability and biological activity on cell behavior for in vitro cell studies. In the area of neuronal regeneration the protein micropatterning and cell choice assays are used to improve our understanding of the mechanisms directing nervous system during development and regenerative failure in the central nervous system (CNS) wound healing environment. In these cell assays, protein micropatterns need to be characterized for protein stability, bioactivity, and spatial distribution and then correlated with observed mammalian cell behavior using appropriate model system for CNS development and repair. This review provides the background on protein micropatterning for cell choice assays and describes some novel patterns that were developed to interrogate neuronal adaptation to inhibitory signals encountered in CNS injuries. Rationale for studying the role of proteoglycans in CNS injuriesNeurons from the central nervous system (CNS) possess a limited capacity to regenerate beyond scar tissue formation barriers in injuries even in the presence of minimal trauma to tissue organization [1,2]. A major culprit in CNS neuronal regenerative failure are the inihibitory proteoglycans (PGs), which are upregulated at the site of CNS injuries. PGs are composed of a core protein with varying numbers of attached glycosaminoglycan (GAG) side chains [3,4]. Proteoglycans are first translated intracellularly into proteins in the endoplasmic reticulum, and then GAG chains are later attached in the Golgi apparatus before secretion into the extracellular space [5][6][7][8]. The study of PGs has particularly been pronounced in the field of neurobiology and development of the nervous system. Numerous studies have concluded that PGs act as barriers that direct the migration of neural crest cells and the outgrowth direction of pathfinding neurons during development [9][10][11][12][13][14][15][16][17]. A number of these studies have additionally shown that cell guidance by PGs is based on an inhibitory signal located within the chondroitin sulfate GAG chains [9,18,19], with the result that the artificial addition of chondroitin sulfate (CS) sugars to the developing nervous system disrupts normal pathfinding [20] as well as does the removal of chondroitin sulfate chains through enzymatic treatment [9,19]. Davies et al. found that chondroitin sulfate proteoglycans (CSPG) are a major constituent of the glial scar and that dorsal root ganglion (DRG) outgrowth termination coincided with an increase in CSPG expression density [21]. Other sources have also shown that CSPGs are upregulated after CNS injuries [22][23][24][25].Interestingly, native adult CNS neurons actually posses the intrinsic ability to regenerate when the wound healing environment is prepared by eliminating inhibitory factors [23,26,27]. In additi...

show abstract

MMP-Related Gelatinase Activity Is Strongly Induced in Scar Tissue of Injured Adult Spinal Cord and Forms Pathways for Ingrowing Neurites

Cited by 93 publications

References 34 publications

Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing

Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing

Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

The effects of proteoglycan surface patterning on neuronal pathfinding

Contact Info

Product

Resources

About