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

Abstract

<jats:p content-type="fine-print"><jats:italic>Object.</jats:italic> 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.</jats:p> <jats:p content-type="fine-print"><jats:italic>Methods.</jats:italic> 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.</jats:p> <jats:p content-type="fine-print"><jats:italic>Conclusions.</jats:italic> 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.</jats:p>

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

“…Consistent with our previous findings (Goussev et al, 2003), MMP-2 was not detected in the wild-type mice 3 d after injury but was strongly detected at 7 and 14 d after injury, with protease bands corresponding to the active form of MMP-2 and the inactive zymogen (proMMP-2) (Fig. 1).…”

“…Two additional wild-type mice received sham surgery and were killed at each of the above time points. Gelatin zymography was performed as described previously (Noble et al, 2002;Goussev et al, 2003). Briefly, segments of the spinal cord containing the lesion epicenter or matched regions of the laminectomy controls were dissected and frozen at Ϫ70°C.…”

“…The glial scar represents not only a physical barrier imposed by massive aggregation of reactive astrocytes (Reier, 1986) but also an inhibitory interface with aberrant expression of chondroitin sulfate proteoglycans (CSPGs), molecules that chemically arrest the regrowth of injured axons across the lesion site (McKeon et al, 1991(McKeon et al, , 1999Levine, 1994). MMP-2 is upregulated concurrently with the emergence of reactive astrogliosis after spinal cord injury (Goussev et al, 2003) and is capable of degrading specific CSPGs . However, whether MMP-2 participates in the formation of a glial scar remains essentially unknown.…”

“…One plausible explanation is that certain MMPs, expressed during wound healing, support recovery processes. A likely candidate is MMP-2, which is the dominant gelatinase in the injured cord during wound healing (Goussev et al, 2003).…”

Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal–astrocytic co-cultures

“…In vivo studies of brain and spinal cord injury have characterized the time-course and degree of inflammation and reactive astrogliosis, providing insight into the physiology of reactive astrocytes and associated matrix alterations (Mathewson and Berry, 1985;Janeczko, 1989;Cervos-Navarro and Lafuente, 1991;Fitch et al, 1999;McKeon et al, 1999;Goussev et al, 2003;Moon et al, 2004). Such in vivo models aid in characterizing the complex reactive astrogliotic response; however, the distinction between causative factors and epiphenomena surrounding the isolation of induction mechanisms remains challenging.…”