Matrix metalloproteinases in neuroinflammation and cerebral ischemia.
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Animals↗
Biomedical subjects
G A Rosenberg
Publications and source records attributed to G A Rosenberg.
Vulnerability of mouse cortical neurons to doxorubicin-induced apoptosis is strain-dependent and is correlated with mRNAs encoding Fas, Fas-Ligand, and metalloproteinases.
Cell surface death receptor-mediated neuronal apoptosis, which is a critical component of neurodegeneration, is modulated by matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Doxorubicin (Dox) induces neuronal death by the activation of death receptor pathways. Recently, we demonstrated that Dox-induced neuronal apoptosis is regulated by the balance of MMP-3 and TIMP-3 in rat cortical cultures. Inbred mouse strains exhibit differential susceptibility to cell death stimuli in vivo. Prior to employing transgenic approaches to further investigate the roles of TIMP-3 and MMP-3 in neuronal death, we examined whether inbred mice display strain-dependent vulnerability to Dox. We induced neuronal apoptosis with Dox in primary neuronal cultures established from cerebral cortices of embryonic day 15 C57BL/10 or C57BL/6 mice. Using fluorescence activated cell sorting for neurons, we found that C57BL/6 cortical cultures exhibit a 28% greater neuronal death following Dox treatment than C57BL/10. Real-time PCR of unstimulated cultures revealed that C57BL/10 cortical cultures have reduced basal mRNA levels encoding the pro-apoptotic proteins: Fas, FasL, and TIMP-3, but increased levels of the anti-apoptotic molecule MMP-3 as compared to C57BL/6. Furthermore, C57BL/10 cultures treated with Dox displayed an enhanced induction of mRNA transcripts that encode anti-apoptotic MMPs. These results show that C57BL/10 cortical cultures are more resistant to death receptor-mediated apoptotic cell death as compared to C57BL/6, and suggest that this difference is related to Fas, FasL, and MMP expression. Strain-dependent differences in response to apoptotic stimuli may be an important consideration for developing transgenic models of neurodegeneration.
Animals↗
Tissue inhibitor of metalloproteinases-3 and matrix metalloproteinase-3 regulate neuronal sensitivity to doxorubicin-induced apoptosis.
Metalloproteinase activity at the cell surface influences cellular sensitivity to extrinsic death vs. survival signals in a variety of cell types, through proteolytic shedding of cell surface signalling molecules. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a unique natural metalloproteinase inhibitor that plays a pro-apoptotic role through its ability to inhibit metalloproteinases that proteolytically cleave death receptors and their ligands from the cell surface. To study the convergence of metalloproteinase activity and death receptor signalling in neurons, we established an in vitro model of neuronal apoptosis utilizing the chemotherapeutic drug, doxorubicin (Dox). Primary cultures established from embryonic rat cerebral cortices displayed robust and selective neuronal apoptosis in response to Dox, an effect that was dependent on the activation of the death receptor, Fas. We demonstrate that both TIMP-3 and matrix metalloproteinase-3 (MMP-3) are constitutively expressed by primary cortical neurons in culture, and selectively modulated Fas-mediated neuronal apoptosis induced by Dox. Metalloproteinase inhibition by TIMP-3 was found to be necessary for Dox-induced neuronal death, whereas addition of active MMP-3 markedly attenuated apoptosis and diminished Fas-Fas ligand interaction at the cell surface. These observations implicate a physiological role for the balance of TIMP-3 and MMP-3 activity at the neuronal surface in regulating death receptor sensitivity. The convergence of metalloproteinase activity and death receptor signalling at the cell surface may influence neuronal cell death vs. survival decisions.
Animals↗
Magnetic resonance lipid signals in rat brain after experimental stroke correlate with neutral lipid accumulation.
Proton magnetic resonance spectroscopy (MRS) signals from lipids in brain have been observed to increase after ischemic brain injury. However, neither the chemical identity nor the cellular location of these lipids has been established. The aim of the present study was to identify the origin of MRS lipid signals in rat brain after temporary (90 min) middle cerebral artery occlusion (MCAO). Fatty acyl proton signals were detected by short-echo one and two dimensional (1)H MRS in superfused brain slices from the infarcted hemisphere 1-5 days after MCAO. The intensities of these signals were strongly correlated with the amount of triacylglyceride and cholesterol ester in lipid extracts from the samples (r(2)=0.96, P<0.05) and were not correlated with the amount of free fatty acids in the tissue. Histological staining of tissue revealed the presence of neutral lipid droplets in infarcted regions. Dual labeling by immunohistochemistry demonstrated that these droplets were localized to microglia/macrophage (OX-42-labeled cells). These results strongly suggest that (1)H MRS lipid signals from brain after stroke arise from microglia/macrophage phagocytosis of cellular membranes.
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Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures.
Reperfusion damages the blood-brain barrier (BBB). Matrix metalloproteinases (MMPs) are associated with the opening of the BBB, but their cellular localization and activation mechanisms are uncertain. We used immunohistochemistry to determine the cellular localization of the MMPs in reperfused rat brain, and cell cultures to study their activation. Spontaneously hypertensive rats (SHR) had a 90 min middle cerebral artery occlusion (MCAO) followed by reperfusion for times from 3 h to 21 days. Frozen sections were immunostained with antibodies to gelatinase A (MMP-2), stromelysin-1 (MMP-3), and gelatinase B (MMP-9). Sham-operated control rats showed MMP-2 immunostaining in astrocytic processes next to blood vessels. After 3 h of the onset of reperfusion MMP-2 immunostaining increased in astrocytes. At 24 h immunoreactivity for MMP-3 and MMP-9 appeared. MMP-3 co-localized with activated microglia (Ox-42+) and ischemic neurons (NeuN+). MMP-9 immunostaining was seen at 48 h in endothelial cells, neutrophils, and neurons. At 5 and 21 days intense MMP-2 staining was seen in reactive astrocytes around the ischemic core. Studies of activation of the MMP were done in lipopolysaccharide (LPS)-stimulated astrocyte and microglia cultures. Stimulated astrocytes produced an activated form of MMP-2. When microglia were stimulated, they activated MMP-9. Immunostaining showed MMP-3 in cultures of enriched microglial cells. The hydroxymate-type, MMP inhibitor, BB-1101, blocked the activation of MMP-2 and MMP-9 by LPS in mixed glial cultures. We propose that MMP-2 is normally present in astrocytic end feet, and that during ischemia MMP-9 and MMP-3 are produced. MMP-3 in microglia/macrophages may be activating proMMP-9. Our results show that a differential expression of MMPs by astrocytes, microglia, and endothelial cells at the blood vessels is involved in the proteolytic disruption of the BBB.
Animals↗
Matrix metalloproteinases in multiple sclerosis: is it time for a treatment trial?
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Humans↗
Matrix metalloproteinases and tissue inhibitors of metalloproteinases in cerebrospinal fluid differ in multiple sclerosis and Devic's neuromyelitis optica.
Matrix metalloproteinases (MMPs) are increased in the CSF of patients with multiple sclerosis. Devic's neuromyelitis optica (DNO) is a demyelinating syndrome that involves the optic nerve and cervical cord but differs pathologically from multiple sclerosis. Therefore, we hypothesized that the type of inflammatory reaction that causes MMPs to be elevated in multiple sclerosis would be absent in patients with DNO. CSF was collected from 23 patients with relapsing-remitting or secondary progressive multiple sclerosis, all of whom were experiencing acute symptoms, from seven patients with DNO, and from seven normal volunteers. Diagnoses were made according to current criteria on the basis of clinical manifestations, imaging results and CSF studies. IgG synthesis was increased in the CSF of multiple sclerosis patients but not in that of DNO patients. Zymography, reverse zymography and ELISA (enzyme-linked immunosorbent assay) were used to measure gelatinase A (MMP-2), gelatinase B (MMP-9) and tissue inhibitors of metalloproteinases (TIMPs). Zymograms showed that multiple sclerosis patients had elevated MMP-9 compared with DNO patients and controls (P: < 0.05). TIMP-1 and TIMP-2 levels were similar in all three groups. We conclude that multiple sclerosis patients have higher MMP-9 levels in the CSF than patients with DNO, which supports the different pathological mechanisms of these diseases.
Humans↗
White matter damage is associated with matrix metalloproteinases in vascular dementia.
BACKGROUND AND PURPOSE: Vascular disease causes multi-infarct dementia (MID) or Binswanger's disease (BD), the latter of which is a progressive form of vascular dementia (VaD) associated pathologically with fibrinoid and hyaline changes in brain arterioles with injury to the white matter. Clinically, BD patients have long-standing hypertension with disturbances of gait and intellect. Because matrix metalloproteinases (MMPs) are important in cerebral infarction, we hypothesized that disturbances in the MMPs may be involved in VAD: METHODS: Brain tissues from 5 patients with VaD of the BD or multi-infarct type (MID) were immunostained with antibodies to glial fibrillary acidic protein (GFAP), a microglial/macrophage cell marker (PG-M1), gelatinase A (MMP-2), stromelysin-1 (MMP-3), and gelatinase B (MMP-9). Control tissues were from 8 elderly patients: 4 with strokes without dementia and 4 without neurological diseases. RESULTS: PG-M1+ cells appeared around infarcts in patients with strokes without dementia and in patients with VAD: In 2 of the 3 BD patients, PG-M1 cells were prominent near damaged arterioles and scattered diffusely in white matter. MMP-2 was seen normally in perivascular macrophages and in astrocytic processes near blood vessels and was present in patients with strokes in reactive astrocytes. MMP-9 was rarely seen. MMP-3 was seen in PG-M1+ microglial/macrophage cells around the acute infarctions. In BD, MMP-3 persisted in tissue macrophages and disappeared in long-standing white matter gliosis. CONCLUSIONS: These observations suggest that MMPs may participate in the damage to the white matter associated with VAD: Microglia/macrophage-induced damage, which is amenable to treatment, may be a factor in the progressive forms of VAD:
Aged↗
Percutaneous CT guided resection of osteoid osteoma of the tibial plafond.
Osteoid osteomas of the foot and ankle are relatively rare and notoriously difficult to diagnose. Juxta-articular osteoid osteomas are more difficult to treat and often have a significant delay in diagnosis. We report a case of a juxta-articular osteoid osteoma of the tibial plafond. Once the diagnosis was made, excisional biopsy was performed percutaneously under computed tomography (CT) guidance as an outpatient in the radiology suite. The patient had complete resolution of symptoms and remains pain free at two years follow-up. CT guided resection can be a lower morbidity and more cost effective technique to treat this lesion than traditional methods.
Biopsy, Needle↗
Matrix metalloproteinases in multiple sclerosis: targets of therapy or markers of injury?
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Adjuvants, Immunologic↗
Extracellular matrix degradation by metalloproteinases and central nervous system diseases.
Matrix metalloproteinases (MMPs) are a gene family of neutral proteases involved in normal and pathological processes in the central nervous system (CNS). Normally released into the extracellular space, MMPs break down the extracellular matrix (ECM) to allow cell growth and to facilitate remodeling. Proteolysis becomes pathological when the normal balance between the proteases and their inhibitors, tissue inhibitors to metalloproteinases (TIMPs), is lost. Cancer cells secrete neutral proteases to facilitate spread through the ECM. MMPs increase capillary permeability, and they have been implicated in demyelination. Neurological diseases, such as brain tumors, multiple sclerosis, Guillain-Barré, ischemia, Alzheimer's disease, and infections, lead to an increase in the matrix-degrading proteases. Two classes of neutral proteases have been extensively studied, namely the MMPs and the plasminogen activators (PAs), which act in concert to attack the ECM. After proteolytic injury occurs, the process of ECM remodeling begins, which can lead to fibrosis of blood vessels and gliosis. TIMPs are increased after the acute injury and may add to the fibrotic buildup of ECM components. Thus, an imbalance in proteolytic activity either during the acute injury or in recovery may aggravate the underlying disease process. Agents that affect the proteolytic process at any of the regulating sites are potentially useful in therapy.
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Radiation-induced blood-brain barrier damage in astrocytoma: relation to elevated gelatinase B and urokinase.
Successful management of brain tumors prolongs life, raising the risk of delayed injury secondary to the treatment. Radiation therapy, a mainstay of brain tumor treatment, can damage the cerebral blood vessels. Acutely a breakdown of the blood-brain barrier (BBB) may be seen, but fibrosis complicates radiation injury in the chronic phase. Matrix metalloproteinases (MMPs) and plasminogen activators are two matrix-degrading proteolytic enzymes, which are induced by radiation. They disrupt the basal lamina around cerebral capillaries and open the BBB. We report a patient with an astrocytoma managed by partial resection and external beam irradiation to maximal tolerable doses. The patient later developed malignant brain edema shortly after stereotactic radiosurgery. Tissue obtained during surgical debulking to control the edema showed very high levels of gelatinase B (92 kDa type IV collagenase) and urokinase-type plasminogen activator (uPA). Tumor cells were absent from the biopsy and subsequent autopsy specimens, but necrosis with fibrosis of the blood vessels was seen. If abnormal matrix enzyme function participates in the expression of radiation injury, then inhibitors to such enzymes may provide one strategy for controlling cerebrovascular damage after therapeutic brain radiation.
Adult↗
Checkrein deformity--an unusual complication associated with a closed Salter-Harris Type II ankle fracture: a case report.
This article presents a case of tethering of the flexor hallucis longus (FHL) tendon (checkrein deformity) and rupture of the posterior tibialis tendon after a closed Salter-Harris Type II ankle fracture. Delayed repair was affected by tenolysis of the FHL and flexor digitorum longus tendons and tenodesis of the posterior tibialis to the flexor digitorum longus tendon. This case represents the first such report of concomitant entrapment of the FHL tendon and rupture of the posterior tibialis tendon after a closed ankle fracture.
Adolescent↗
Matrix metalloproteinases in cerebrovascular disease.
Cerebral ischemia and intracerebral hemorrhage cause extensive damage to neurons, disrupt the extracellular matrix, and increase capillary permeability. Multiple substrates participate in the cellular damage, including free radicals and proteases. Matrix metalloproteinases and serine proteases are two classes of proteases that are normally present in brain in latent forms, but once activated, contribute to the injury process. These enzymes have a unique role in the remodeling of the extracellular matrix and in the modulation of the capillary permeability. Intracerebral injection of the matrix metalloproteinase, type IV collagenase, attacks the basal lamina around the capillary and opens the blood-brain barrier. Extracellular matrix-degrading proteases are induced by immediate early genes and cytokines, and regulated by growth factors. Activity of the matrix metalloproteinases is tightly controlled by activation mechanisms and tissue inhibitors of metalloproteinases. During ischemia and hemorrhage, multiple matrix metalloproteinases and serine proteases are produced along with their inhibitors. These proteolytic enzymes are involved in the delayed injury that accompanies the neuroinflammatory response. Synthetic inhibitors to metalloproteinases reduce proteolytic tissue damage, and may limit secondary neuroinflammation.
Animals↗
Gelatinase B modulates selective opening of the blood-brain barrier during inflammation.
Matrix metalloproteinases (MMPs) are associated with neuroinflammatory diseases, and blood-brain barrier damage is a pathophysiological consequence of central nervous system inflammation. We examined whether an increase in MMP production is coupled with the breakdown of blood-brain barrier integrity in the lipopolysaccharide (LPS)-injured brain. Rat brain stimulated with LPS showed a significant rise in gelatinase B (MMP-9) production at 24 h compared with either tumor necrosis factor-alpha (TNF-alpha) or saline-injected controls. Latent 92-kDa gelatinase B was detected by 4 h, peaked at 8 h, and persisted for 24 h after LPS injection. Production of the active 84-kDa form of gelatinase B was less pronounced, but paralleled 92-kDa enzyme expression. Breakdown in blood-brain barrier integrity, measured by the infiltration of radiolabeled exogenous markers into the brain, was significant to [14C]sucrose (molecular mass 342 Da) and injected animals compared with saline-injected controls. The extent of MMP involvement in barrier permeability was examined in animals treated with the MMP inhibitor BB-1101. A significant drop in gelatinase A and B production was detected in LPS-injured animals receiving BB-1101 compared with untreated animals. This MMP inhibitor also reduced [14C]sucrose uptake in LPS-injected animals, but had no effect on [14C]dextran uptake. MMP production is upregulated in LPS-injured brain tissue and is instrumental in regulating the size-differentiated opening of the blood-brain barrier during acute neuroinflammation.
Animals↗
Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain.
BACKGROUND AND PURPOSE: Reperfusion disrupts cerebral capillaries, causing cerebral edema and hemorrhage. Middle cerebral artery occlusion (MCAO) induces the matrix-degrading metalloproteinases, but their role in capillary injury after reperfusion is unknown. Matrix metalloproteinases (MMPs) and tissue inhibitors to metalloproteinases (TIMPs) modulate capillary permeability. Therefore, we measured blood-brain barrier (BBB) permeability, brain water and electrolytes, MMPs, and TIMPs at multiple times after reperfusion. METHODS: Adult rats underwent MCAO for 2 hours by the suture method. Brain uptake of 14C-sucrose was measured from 3 hours to 14 days after reperfusion. Levels of MMPs and TIMPs were measured by zymography and reverse zymography, respectively, in contiguous tissues. Other rats had water and electrolytes measured at 3, 24, or 48 hours after reperfusion. Treatment with a synthetic MMP inhibitor, BB-1101, on BBB permeability and cerebral edema was studied. RESULTS: Brain sucrose uptake increased after 3 and 48 hours of reperfusion, with maximal opening at 48 hours and return to normal by 14 days. There was a correlation between the levels of gelatinase A at 3 hours and the sucrose uptake (P<0.05). Gelatinase A (MMP-2) was maximally increased at 5 days, and TIMP-2 was highest at 5 days. Gelatinase B and TIMP-1 were maximally elevated at 48 hours. The inhibitor of gelatinase B, TIMP-1, was also increased at 48 hours. Treatment with BB-1101 reduced BBB opening at 3 hours and brain edema at 24 hours, but neither was affected at 48 hours. CONCLUSIONS: The initial opening at 3 hours correlated with gelatinase A levels and was blocked by a synthetic MMP inhibitor. The delayed opening, which was associated with elevated levels of gelatinase B, failed to respond to the MMP inhibitor, suggesting different mechanisms of injury for the biphasic BBB injury.
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Limb salvage versus amputation for severe open fractures of the tibia.
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Aged↗
Neutral proteases and disruption of the blood-brain barrier in rat.
Blood-brain barrier disruption is common in many neurological diseases. Matrix metalloproteinases are induced in brain injury and increase capillary permeability by attacking the extracellular matrix around cerebral capillaries. Other neutral proteases are also increased in sites of secondary injury, and may contribute to the proteolysis of the blood-brain barrier. Therefore, we studied capillary permeability and histological tissue damage after intracerebral injection of neutrophil elastase, cathepsin G, heparatinase and plasmin. Adult rats were injected intracerebrally with an enzyme. After 1, 4 or 24 h, measurements were made of brain uptake of a radiolabeled tracer, [14C]sucrose. Enzymes that significantly increased capillary permeability were injected into other rats for histological assessment of tissue damage. Elastase increased capillary permeability significantly when compared with controls; maximal damage was seen at 4 h. Plasmin produced smaller increases in permeability at 4 h, exerting its maximal effect on sucrose uptake at 24 h. Cathepsin G had a small effect at 4 h. Heparitinase had no effect. Histologic examination of elastase-injected brains at 24 h revealed multifocal perivascular and intraparenchymal acute hemorrhages accompanied by a polymorphonuclear cell infiltrate. Elastase-injected brains were microscopically similar to saline-injected brains at 1 and 4 h. Plasmin produced fibrinoid changes in the blood vessels at 24 h, coinciding with the maximal increase in capillary permeability. We conclude that neutrophil elastase attacks the capillary extracellular matrix, causing extensive hemorrhage, while plasmin leads to increased vascular permeability and fibrinoid necrosis of blood vessel walls. Differential effects of neutral proteases released secondary to injury could be important in both the acute changes in blood vessel permeability and long-term alterations in vessel structure.
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