Brain, Vol. 122, No. 2, 191-197,
February 1999
© 1999 Oxford University Press
Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis
A longitudinal clinical and MRI study
1 Department of Clinical Neurology, The Radcliffe Infirmary and 2 British Biotech Pharmaceuticals Ltd, Oxford, UK
Correspondence to:
Dr J. Palace, Department of Clinical Neurology, The Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HG, UK
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Abstract |
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Metalloproteinases have been implicated in the pathogenesis of multiple sclerosis. We report longitudinal serum levels of gelatinase B and of the tissue inhibitors of matrix metalloproteinases (TIMP), TIMP-1 and TIMP-2, in 21 patients with relapsing multiple sclerosis. Patients had monthly clinical and gadolinium-enhanced MRI follow-up for 10 months. Longitudinal samples in nine healthy controls and cross-sectional samples from 12 patients with inflammatory CNS disease and 15 patients with other neurological diseases were used for comparison. Average serum gelatinase B, TIMP-1 and TIMP-2 levels were significantly higher in multiple sclerosis patients and those with other neurological diseases than in healthy controls. In the patients with multiple sclerosis, gelatinase B levels were significantly higher during clinical relapse compared with periods of clinical stability. Multiple sclerosis patients with high mean serum gelatinase B levels had significantly more T1-weighted gadolinium-enhancing MRI lesions than those with mean levels within the control range. TIMP-1 levels were not different during relapse and between relapses. There was a trend for TIMP-2 levels to be lower during relapse compared with non-relapse periods. For similar levels of serum gelatinase B, associated TIMP-1 levels were significantly lower and TIMP-2 levels significantly higher in multiple sclerosis patients compared with the inflammatory CNS control group. We propose that an abnormality in the inhibitory response to metalloproteinases may play an aetiological role in the chronicity of multiple sclerosis.
matrix metalloproteinases; multiple sclerosis; TIMP and MRI
EDSS = expanded disability status scale; ELISA = enzyme-linked immunosorbent assay; MMP = matrix metalloproteinase; TIMP = tissue inhibitor of matrix metalloproteinases
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Introduction |
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Multiple sclerosis is an inflammatory disease of the CNS for which the exact immunopathogenic mechanisms underlying disease initiation and progression are not known. Many cytokines are upregulated in the blood of patients with multiple sclerosis (Navikas and Link, 1996
; Hermans et al., 1997) but are also increased in other inflammatory neurological diseases (Feuerstein et al., 1994; Arvin et al., 1996). Factors that might differentiate the chronic, relapsing inflammatory profile seen in multiple sclerosis from more acute monophasic inflammatory conditions of the CNS are not well defined.
Matrix metalloproteinases (MMPs) are a large group of proteolytic enzymes involved in degrading and remodelling the extracellular matrix in response to a number of pathological conditions (Banik, 1992; Kleiner et al., 1993). These potentially destructive enzymes are tightly regulated to prevent unwanted tissue damage by controlling gene transcription and proenzyme activation and, once activated, by forming complexes with tissue inhibitors of MMPs (TIMPs) (Kleiner et al., 1993). There is growing evidence that upregulation of MMP expression, and in particular the 92-kDa metalloproteinase, gelatinase B, contributes to tissue destruction and cellular trafficking across the blood–brain barrier in multiple sclerosis (Goetzl et al., 1996; Chandler et al., 1997). Gelatinase B expression in the CSF of animals with experimental autoimmune encephalitis correlates with clinical score (Clements et al., 1997). MMPs are involved in the processing of a number of proinflammatory cytokines implicated in the pathogenesis of multiple sclerosis, such as tumour necrosis factor-
(Gearing et al., 1994). Studies in animals have shown that gelatinase B produced in response to injection with tumour necrosis factor- modulates the opening of the blood–brain barrier, an effect inhibited by TIMP-2 (Rosenberg et al., 1992, 1995). Raised levels of gelatinase B have been detected in the CSF of patients with multiple sclerosis (Gijbels et al., 1992; Paemen et al., 1994) and in multiple sclerosis plaques (Maeda and Sobel, 1996; Cuzner et al., 1996) and confirmed by Anthony et al. (1997). Recently it has been shown that elevated levels of gelatinase B in the CSF fall following steroid treatment for clinical relapse in multiple sclerosis (Rosenberg et al., 1996). However, the exact pathogenic importance of the MMPs, and in particular gelatinase B, in multiple sclerosis is still unclear. Even less well elucidated are the patterns and significance of TIMP expression in multiple sclerosis.
We have demonstrated recently that gelatinase B can be detected in the serum of patients with multiple sclerosis and other inflammatory diseases (Miller et al., 1996). This has allowed us to monitor longitudinal changes in the MMP axis in relation to clinical and MRI markers of disease activity. We report the results of a prospective longitudinal study measuring gelatinase B, TIMP-1 and TIMP-2 in 21 patients with relapsing–remitting multiple sclerosis by enzyme-linked immunosorbent assay (ELISA). We relate these results to clinical and MRI parameters. Comparison is made also with longitudinal samples from healthy controls and cross-sectional samples from patients with acute inflammatory CNS conditions and non-inflammatory neurological disease.
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Method |
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Patients
Twenty-one patients with relapsing–remitting multiple sclerosis were recruited with an expanded disability status scale (EDSS) score between 2 and 5.5 inclusive. All patients were also involved in a phase-2 trial approved by the Central Oxford Research Ethics Committee and had given informed consent. The trial was double-blind, placebo-controlled and crossover in design, so that all patients had equal exposure to the oral agent involved. Subsequent analysis (unpublished) showed that there were no significant differences between serum levels of gelatinase B, inhibitors TIMP-1 and TIMP-2 or MRI markers of disease activity during treatment and placebo periods. The oral agent involved was not believed to be immunosuppressive or have any effect on MMP production and activity. Patients had been clinically stable for 1 month prior to entry into the study. Clinical assessment (including EDSS), standard-dose gadolinium-enhanced brain MRI and serum samples for ELISA were done on a monthly basis (within 24 h of each other) for 10 months, with non-scheduled visits arranged if patients suffered a relapse. Relapse was defined as the onset of new or recurrent symptoms or signs lasting >24 h in the absence of fever. The number of gadolinium-enhancing T1-weighted MRI lesions was identified on the monthly scans. Longitudinal serum samples were taken in nine healthy volunteers on a monthly basis and during episodes of systemic illness such as viral infection. Cross-sectional samples were taken from 12 patients with CNS conditions associated with a marked inflammatory response, including encephalitis, bacterial meningitis, cerebral abscess and subarachnoid haemorrhage. Fifteen patients with chronic neurological disorders without significant CNS inflammation, including Alzheimer's disease, epilepsy, Parkinson's disease and myasthenia gravis, also had samples taken for preliminary comparison. None of the latter group were receiving immunosuppressive treatment. Samples from the 12 patients with CNS conditions associated with an inflammatory response and from 12 multiple sclerosis patients matched for gelatinase B levels had serum levels of the 72-kDa MMP, gelatinase A, measured by ELISA.
MRI parameters
All scans were performed with the same 1.5T GE Sigma scanner. Monthly short TR (repetition time) spin echo sequences [TR 400 ms, TE (echo time) 13 ms, twenty-four 5-mm contiguous axial slices] were performed both before and 5 min after injection of standard-dose gadolinium-diethylenetriamine pentaacetic acid (0.1 mmol/kg). Lesions were identified by a single-blinded observer.
Assay for gelatinase B, gelatinase A, TIMP-1 and TIMP-2
Blood samples were spun immediately and serum was stored at –20°C for a maximum of 48 h before being stored at –70°C prior to analysis using a sandwich ELISA. In ELISA for gelatinase B, a murine monoclonal capture antibody against human recombinant gelatinase B purified from transfected CHO cell supernatant was used (British Biotech Pharmaceuticals, Oxford, UK). Ninty-six-well plates (Maxisorb; Nunc, Roskilde, Denmark) were coated with the antibody at a concentration of 2.5 µg/ml in 0.05 M carbonate/bicarbonate buffer (pH 9.6), 100 µl/well, for 16 h at 4°C. The plates were washed with PBS (phosphate-buffered saline) (without Mg2+ and Ca2+), then blocked with PBS + 1% BSA for 1 h at 4°C. The plates were then washed with PBS containing 0.1% Tween-20. Samples of serum (100 µl) diluted 1 : 20 were added to duplicate wells. A standard curve was derived from human recombinant gelatinase B produced in transfected CHO cells in PBS/0.1% Tween-20. The plates were incubated at room temperature for 2 h, washed with PBS/0.1% Tween-20 and incubated with a peroxidase-conjugated sheep anti-human gelatinase B polyclonal antibody (0.35 mg /ml; British Biotech Pharmaceuticals) for 1 h at room temperature. The plates were washed with PBS/0.1% Tween-20, then incubated with 100 µl TMB Microwell Peroxidase Substrate (Kirkegaard & Perry Laboratories, Gaithersburg, Maryland, USA) for 10 min at room temperature. The reaction was stopped by the addition of 1.0 M HCl at 50 µl/well, and the absorbance was measured using a microplate reader (Anthos Labtec, Ringmer, East Sussex, UK) at 450 nm, with a reference of 620 nm. Serum gelatinase B levels were calculated from the standard curve.
The sandwich ELISA protocol for gelatinase A was similar to that for gelatinase B, instead using a monoclonal capture antibody, 6H8, raised against human recombinant human gelatinase A (British Biotech Pharmaceuticals) at 5 µg/ml and a peroxidase-conjugated sheep anti-human gelatinase A polyclonal antibody (0.35 µg/ml; British Biotech Pharmaceuticals) for detection.
Specificity controls were performed on the monoclonal capture antibodies of the two-site ELISAs as follows. The monoclonal antibody to gelatinase B bound gelatinase B by immunoblotting and when coated on ELISA plates, but showed no binding by either method to gelatinase A, stromolysin, matrilysin, macrophage metalloelastase or collagenase. The monoclonal antibody to gelatinase A bound to this protein during immunoblotting and when coated on ELISA plates, but showed no binding by either method to gelatinase B, stromolysin or matrilysin.
ELISAs for TIMP-1 and TIMP-2 were purchased from Amersham (Little Chalfont, Bucks, UK) and used according to the manufacturer's instructions. Biochemical analysis was performed with blinding to clinical and MRI details.
Outcome measures
Mean serum gelatinase B, TIMP-1 and TIMP-2 levels were calculated in the healthy controls and in patients with multiple sclerosis and with CNS conditions with and without an inflammatory response. Mean gelatinase B, TIMP-1 and TIMP-2 levels were compared during and outside of clinical relapse in individual multiple sclerosis patients. Gadolinium-enhanced MRI activity was also compared with gelatinase B levels in multiple sclerosis patients. TIMP levels in patients with CNS conditions associated with an inflammatory response were directly compared with TIMP levels in samples from multiple sclerosis patients matched for gelatinase B levels. Gelatinase A levels were also measured in these matched patients. Cross-group comparisons were made using Wilcoxon's signed rank test and tested for correlation with Spearman's ranked measure. Comparison of enzyme levels during and between periods of relapse within patients was performed using a paired t test.
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Results |
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Clinical data are summarized in Table 1
. Fifteen of 21 patients suffered a total of 25 relapses during the study year, no patient having more than three relapses. Four relapses (16%) were treated with intravenous steroids during the study.
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Mean serum gelatinase B levels were significantly higher in patients with multiple sclerosis (454 ± 412 ng/ml, P < 0.001) and those with CNS disorders with (646 ± 240 ng/ml, P = 0.02) and without (333 ± 280 ng/ml, P = 0.01) an inflammatory response compared with the healthy control group (122 ± 106 ng/ml) (Fig. 1
). Mean serum gelatinase B levels were not significantly different (P = 0.75) between multiple sclerosis patients from our study cohort and in 19 treatment-naive multiple sclerosis patients sequentially selected from the out-patient clinic (454 ± 412 compared with 486 ± 116 ng/ml). Mean levels of gelatinase B were higher in patients with CNS conditions associated with an inflammatory response than in those with multiple sclerosis but this difference did not reach statistical significance, possibly due to the small number of the former patients in the analysis (12). Serum gelatinase B levels fluctuated from month to month in some patients in the multiple sclerosis group (maximum intrapatient range, 34 to >1250 ng/ml), but also in some healthy control subjects (maximum intrasubject range, 0–665 ng/ml). Overall, mean gelatinase B levels did not correlate significantly with EDSS or EDSS divided by time from first symptoms in multiple sclerosis patients.
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To better define the relationship between serum gelatinase B level and disease activity in multiple sclerosis, gelatinase B levels were compared during and outside clinical relapse in the 15 patients who suffered a relapse. Of these, 12 had mean gelatinase B levels higher during relapse than outside of relapse. Analysis of mean levels within patients showed that levels during relapse were significantly higher (P = 0.02, paired t test) (Fig. 2
). Additionally, multiple sclerosis patients with `high' mean serum gelatinase B levels [n = 10, defined as 2 SD above the mean healthy control level (335 ng/ml)] had significantly more (3.6 compared with 0.98, P = 0.001) gadolinium-enhancing lesions per scan than patients with `normal' mean serum gelatinase B levels (n = 11) (Fig. 3).
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Mean TIMP-1 levels were significantly lower (P = 0.02) in patients with multiple sclerosis (1872 ± 615 ng/ml) than in those with CNS conditions with an inflammatory response (3502 ± 1533 ng/ml), but higher than in healthy controls (1202 ± 427 ng/ml, P < 0.001) (Fig. 4A
). However, the opposite pattern was seen for TIMP-2 levels, which were significantly higher (P = 0.01) in multiple sclerosis patients (167 ± 251 ng/ml) than in both CNS patients with an inflammatory response (55 ± 20 ng/ml) and healthy control subjects (34 ± 14 ng/ml) (Fig. 4B). There was no difference in TIMP-1 levels during and outside clinical relapse (P = 0.4). In contrast, there was a trend (P = 0.09) for TIMP-2 levels to be higher outside than during clinical relapse.
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In order to compare the inhibitor response in multiple sclerosis with that in CNS patients with an inflammatory response, levels of TIMP-1 and TIMP-2 were compared with gelatinase B levels in all samples from these two groups (Fig. 5A and B
). Further analysis was done by matching 12 serum samples from the multiple sclerosis study group with gelatinase B levels closest to those of the inflammatory CNS control group values (mean difference, 14 ng/ml; range, 0–57 ng/ml). Matched TIMP-1 levels were lower in multiple sclerosis patients than in inflammatory controls (P = 0.02) (Fig. 6A). There was a significant positive correlation between TIMP-1 levels and gelatinase B levels in the inflammatory CNS group (r = 0.65, P = 0.02), which was not seen with TIMP-1 levels in the multiple sclerosis samples. An opposite pattern was seen with TIMP-2 levels in the matched samples: TIMP-2 levels were significantly higher in multiple sclerosis patients compared with the inflammatory CNS group (P = 0.01) (Fig. 6B). Higher TIMP-2 levels might be explained by gelatinase A levels (often tightly associated with TIMP-2). However, gelatinase A levels for the matched samples were significantly lower in patients with multiple sclerosis (2581 ± 677 ng/ml) than in the inflammatory CNS group (3185 ± 265 ng/ml) (P = 0.03).
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Discussion |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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MMPs are thought to play an important role in neuroinflammatory conditions. In multiple sclerosis they have been implicated in promoting T-cell migration across the blood–brain barrier, demyelination and local tissue destruction (Chandler et al., 1997
). To date, enzyme profiles have been investigated primarily using CSF and brain parenchyma, making serial studies difficult. We have demonstrated that gelatinase B can be detected in the serum by ELISA and have related longitudinal measurements to clinical and MRI data. Mean serum gelatinase B levels were significantly raised in patients with multiple sclerosis compared with healthy controls. Levels in patients with other inflammatory conditions were also higher than those in healthy controls.
Significantly higher levels of gelatinase B were seen during clinical relapse compared with non-relapse periods. Patients with high mean serum gelatinase B levels had significantly more new T1-weighted gadolinium-enhancing lesions than patients with levels within the normal range. Our findings are consistent with the hypothesis that raised gelatinase B levels play a role in blood–brain barrier breakdown in vivo and are consistent with previous findings of increased MMP expression in areas of acute inflammation in multiple sclerosis (Cuzner et al., 1996; Maeda and Sobel, 1996; Anthony et al., 1997).
The balance between the production and activity of MMPs and the production of TIMPs within a tissue is likely to determine the amount of inflammatory destruction. We have observed differences in this balance between patients with multiple sclerosis and those with other inflammatory CNS diseases. Our observations suggest that TIMP-1 levels may be attenuated in multiple sclerosis, especially in response to high levels of gelatinase B. The impression of reduced TIMP-1 expression in relation to gelatinase B expression has also been suggested by other workers (Cuzner et al., 1996) using immunohistochemical techniques. In contrast, we found that TIMP-2 levels were elevated in multiple sclerosis patients compared with the inflammatory neurological controls. There is evidence that TIMP-2 may be co-regulated with gelatinase A (Edwards et al., 1996; Murphy et al., 1997). However, despite having higher TIMP-2 levels, multiple sclerosis patients had significantly lower gelatinase A levels than those found in the inflammatory neurological control group. There was a trend for TIMP-2 levels to be depressed during clinical relapse, an effect that may reflect an inability to upregulate TIMP-2 sufficiently to offset increased TIMP utilization during periods of intense inflammatory activity.
These findings provide preliminary evidence that the TIMP response in multiple sclerosis is different from that of monophasic inflammatory CNS conditions. This possible switch from a TIMP-1-predominant pattern in acute inflammatory conditions to a TIMP-2-predominant pattern in multiple sclerosis needs confirmation.
How an altered pattern of TIMP production might contribute to the chronic inflammatory picture seen in multiple sclerosis is unclear. However, although considerable overlap exists, TIMP-1 preferentially inhibits gelatinase B whilst TIMP-2 has a preference for gelatinase A. Hence, a compensatory TIMP-2-predominant pattern of inhibitor response in multiple sclerosis might result in less effective and incomplete inhibition of gelatinase B. Such a scenario might result in breakdown of the blood–brain barrier and continuous degradation of myelin components, with the generation of multiple immunogenic epitopes and a persistent inflammatory response (Proost et al., 1993).
The exact source of gelatinase B, TIMP-1 and TIMP-2 measured in the serum from multiple sclerosis patients is not known. Many cells can secrete MMPs in culture, including leucocytes, astrocytes and microglia (Apodaca et al., 1990; Colton et al., 1993), and expression in these cell types is upregulated in multiple sclerosis (Sobel et al., 1995; Maeda et al., 1996; Anthony et al., 1997). Serum MMP levels in vivo may directly reflect inflammatory cell activity within the CNS by leakage back across a disrupted blood–brain barrier. Alternatively, rises in serum MMPs may represent peripheral T cell activation.
In summary, ELISA quantification of MMPs and their inhibitors in serum appears to be sufficiently sensitive to provide a simple method for monitoring enzyme levels longitudinally and should prove useful in characterizing patterns of proteolytic enzyme production in different inflammatory conditions. The present study is the first, to our knowledge, to report longitudinal serum measurements of gelatinase B, TIMP-1 and TIMP-2 in multiple sclerosis and to relate the levels to clinical and MRI markers of disease activity. Results show that levels of gelatinase B are increased in multiple sclerosis and that these levels reflect disease activity. We also provide preliminary evidence for a pattern of TIMP response in multiple sclerosis distinct from that seen in acute monophasic inflammatory CNS conditions. Such findings suggest that MMPs may play a key role in the pathogenesis of multiple sclerosis and support the testing of MMP inhibitors in clinical trials. Further elucidation of MMP–inhibitor interactions may allow more specific therapeutic targeting in the future.
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Acknowledgments |
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The authors wish to thank Mrs Anna Cavey for help with the supervision and collection of samples from multiple sclerosis patients and control subjects.
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Received June 5, 1998. Revised August 6, 1998. Accepted September 25, 1998.
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 G. A. Rosenberg Matrix Metalloproteinases and Neuroinflammation in Multiple Sclerosis Neuroscientist, December 1, 2002; 8(6): 586 - 595. [Abstract] [PDF]
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G M Liuzzi, M Trojano, M Fanelli, C Avolio, A Fasano, P Livrea, and P Riccio Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis Multiple Sclerosis, June 1, 2002; 8(3): 222 - 228. [Abstract] [PDF]
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V. Brundula, N. B. Rewcastle, L. M. Metz, C. C. Bernard, and V. W. Yong Targeting leukocyte MMPs and transmigration: Minocycline as a potential therapy for multiple sclerosis Brain, June 1, 2002; 125(6): 1297 - 1308. [Abstract] [Full Text] [PDF]
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 C. A. D'Souza, B. Mak, and M. A. Moscarello The Up-regulation of Stromelysin-1 (MMP-3) in a Spontaneously Demyelinating Transgenic Mouse Precedes Onset of Disease J. Biol. Chem., April 12, 2002; 277(16): 13589 - 13596. [Abstract] [Full Text] [PDF]
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I. Nelissen, I. Ronsse, J. Van Damme, and G. Opdenakker Regulation of gelatinase B in human monocytic and endothelial cells by PECAM-1 ligation and its modulation by interferon-beta J. Leukoc. Biol., January 1, 2002; 71(1): 89 - 98. [Abstract] [Full Text] [PDF]
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R. L. P. Lindberg, C. J. A. De Groot, L. Montagne, P. Freitag, P. van der Valk, L. Kappos, and D. Leppert The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis Brain, September 1, 2001; 124(9): 1743 - 1753. [Abstract] [Full Text] [PDF]
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 X. Han, Y. Sun, S. Scott, and D. Bleich Tissue Inhibitor of Metalloproteinase-1 Prevents Cytokine-Mediated Dysfunction and Cytotoxicity in Pancreatic Islets and {beta}-cells Diabetes, May 1, 2001; 50(5): 1047 - 1055. [Abstract] [Full Text]
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B. C. Kieseier, C. Schneider, J. M. Clements, A. J. H. Gearing, R. Gold, K. V. Toyka, and H.-P. Hartung Expression of specific matrix metalloproteinases in inflammatory myopathies Brain, February 1, 2001; 124(2): 341 - 351. [Abstract] [Full Text] [PDF]
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K. A. Harkness, P. Adamson, J. D. Sussman, G. A. B. Davies-Jones, J. Greenwood, and M. N. Woodroofe Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium Brain, April 1, 2000; 123(4): 698 - 709. [Abstract] [Full Text] [PDF]
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E. Waubant, D. E. Goodkin, L. Gee, P. Bacchetti, R. Sloan, T. Stewart, P.-B. Andersson, G. Stabler, and K. Miller Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis Neurology, October 22, 1999; 53(7): 1397 - 1397. [Abstract] [Full Text] [PDF]
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B. C. Kieseier, T. Seifert, G. Giovannoni, and H.-P. Hartung Matrix metalloproteinases in inflammatory demyelination: Targets for treatment Neurology, July 1, 1999; 53(1): 20 - 20. [Abstract] [Full Text]
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G. Opdenakker Metalloproteinases and specific inhibitors in multiple sclerosis: from blood to brain or vice versa? Brain, February 1, 1999; 122(2): 181 - 182. [Full Text] [PDF]
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