Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators

Yong, V. Wee; Zabad, Rana; Agrawal, Smriti; DaSilva, Angelika Goncalves; Metz, Luanne M.

doi:10.1016/j.jns.2006.11.021

Cited by 150 publications

(134 citation statements)

References 56 publications

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“…For the most part MMPs are considered detrimental in MS and EAE promoting an inflammatory milieu within the CNS, which ultimately results in demyelination and disease exacerbation. 40,51 However, we have documented that the up-regulated MMP-12 in EAE is unique in that its absence leads to a worsened EAE disease course compared with wild-type controls 31 ( Figure 6A). We would suggest that the results of this study provide one mechanism to the benefits of MMP-12 in EAE, which is the processing of OPN into less pro-inflammatory forms.…”

Section: Discussionmentioning

confidence: 93%

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

DaSilva

Liaw

Yong

2010

The American Journal of Pathology

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A role for osteopontin (OPN) in promoting disease activity of multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) has recently been suggested. As the biological activity of OPN is heavily influenced by posttranslational processing, we investigated the capacity of matrix metalloproteinase (MMP)-12 to cleave OPN and determined whether this influenced disease activity. We found that OPN mRNA and protein expression in the spinal cord increased with EAE disease in C57BL/6 mice concurrently with MMP-12 expression. A Western blot of EAE and control spinal cords revealed different OPNimmunoreactive bands, with a pattern that was similar to MMP-12 cleavage of recombinant OPN in vitro. In addition, OPN fragments in the spinal cord of EAEafflicted mice were reduced in MMP-12 ؊/؊ mice compared with wild-type controls. However, examination of OPN ؊/؊ mice in short-and long-term experiments revealed no difference in EAE outcomes from wildtype animals. OPN/MMP-12 double null mice were generated, and it was revealed that MMP-12 ؊/؊ mice had a worsening of disease compared with wild-type mice, which returned to wild-type levels in the OPN/ MMP-12 double null mice. These results suggest that EAE disease activity may be modulated by the cleavage of OPN by

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Section: Discussionmentioning

confidence: 93%

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

DaSilva

Liaw

Yong

2010

The American Journal of Pathology

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“…MMPs are implicated in the pathology of MS and EAE as marked by several lines of evidence (Hartung and Kieseier, 2000;Yong et al, 2001Yong et al, , 2007Opdenakker et al, 2003). Many members are elevated in the serum, CSF, and brain tissue of patients with MS (for review, see Yong et al, 2007) and in the CNS of mice afflicted with EAE (Weaver et al, 2005;Toft-Hansen et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Many members are elevated in the serum, CSF, and brain tissue of patients with MS (for review, see Yong et al, 2007) and in the CNS of mice afflicted with EAE (Weaver et al, 2005;Toft-Hansen et al, 2006). In human subjects, the period between the first and second clinical attacks of MS is accompanied by an increase in levels of MMP-9 in the serum compared with controls (Correale and Bassani Molinas Mde, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The expression of MMPs has consequences, as these proteases influence the activation of T-cells in the periphery (Li et al, 2007), the transmigration of leukocytes into the CNS (Rosenberg, 2002;Toft-Hansen et al, 2004;Agrawal et al, 2006), and demyelination and axonal/neuronal loss within the CNS (Matyszak and Perry, 1996;Newman et al, 2001). In support, pharmacological inhibitors (e.g., GM6001, Ro31-9790, and BB1101) of MMPs alleviate the clinical course and neuropathology of EAE (for review, see Yong et al, 2007). Moreover, EAE is reduced in mice that are genetically deficient for MMP-2, -7, -8, and -9 (Dubois et al, 1999;Agrawal et al, 2006;Folgueras et al, 2008;Buhler et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Agrawal¹,

Silva²,

Tourtellotte³

et al. 2011

J. Neurosci.

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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the Ig superfamily, with various physiological roles including the induction of matrix metalloproteinases (MMPs), leukocyte activation, and tumor progression. In this study, we illustrate a novel involvement of EMMPRIN in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We found EMMPRIN levels to be upregulated on peripheral leukocytes before onset of EAE clinical signs and on infiltrating leukocytes and resident cells within the CNS in symptomatic mice. In EAE brain sections, EMMPRIN expression was localized with MMP-9 protein and activity. The increased EMMPRIN level was also characteristic of brain samples from MS subjects, particularly in plaque-containing areas. To evaluate the implications of elevated EMMPRIN levels, we treated EAE mice with an EMMPRIN function-blocking antibody and found reduced EAE clinical severity accompanied by decreased CNS parenchymal infiltration of leukocytes. Amelioration of EAE clinical signs by the anti-EMMPRIN antibody was critically dependent on its administration around the period of onset of clinical signs, which is typically associated with significant influx of leukocytes into the CNS. Moreover, the reduction in disease severity in anti-EMMPRINtreated mice was associated with diminished MMP proteolytic activity at the glia limitans, the final barrier before parenchymal infiltration of leukocytes. Together, our results are the first to emphasize a role for EMMPRIN in MS and EAE, whereby EMMPRIN regulates leukocyte trafficking through increasing MMP activity. These results identify EMMPRIN as a novel therapeutic target in MS.

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“…Increased MMPs activity might be one of the factors that cause progression of MS disease (5). Imbalance in the level of these enzymes has been detected in the serum and cerebrospinal fluid (CSF) of MS patients (6)(7)(8). These enzymes have a key role in the destruction of the blood-brain barrier (BBB) and central nervous system (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

The Association Between Matrix Metalloproteinase-7 A-181G Polymorphism and the Risk of Relapsing-Remitting Multiple Sclerosis in Iranian Kurdish Patients from Kermanshah

Mohammadi¹,

Rahimi²,

Rahimi³

2015

Avicenna J Med Biochem

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Background: Multiple sclerosis (MS) is a common chronic genetic disease of the central nervous system. The relapsing-remitting-MS (RR-MS) is the most common form of this disease. Matrix metalloproteinase-7 (MMP-7) is an important member of the MMP family, which degrades many extracellular matrix components. The common polymorphism of MMP-7 A-181G is associated with some diseases. Objectives: The aim of the present study was to determine the influence of this polymorphism on the risk of RR-MS. Materials and Methods: Eighty RR-MS patients and 80 healthy individuals as controls from the Kermanshah province were studied for MMP-7 A-181G polymorphism by using the PCR-RFLP method. Data were analyzed using the SPSS statistical software package version 16.0. Results: In RR-MS patients the frequency of MMP-7 GG genotype was significantly (P = 0.028) higher compared to that of the controls. The presence of GG genotype increased the risk of RR-MS by 1.69 times [OR = 1.69 and 95% CI = 1.05-2.72, P = 0.03]. The frequency of MMP-7 G allele in RR-MS patients was significantly higher (51.2%, P = 0.043) than that of the controls (40%). The presence of this allele increased the risk of RR-MS by 1.58 folds (P = 0.044). Conclusions: Our findings indicate that the presence of G allele of MMP-7 A-181G polymorphism might increase the risk of RR-MS in our population.

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Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators

Cited by 150 publications

References 56 publications

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

Cleavage of Osteopontin by Matrix Metalloproteinase-12 Modulates Experimental Autoimmune Encephalomyelitis Disease in C57BL/6 Mice

EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

The Association Between Matrix Metalloproteinase-7 A-181G Polymorphism and the Risk of Relapsing-Remitting Multiple Sclerosis in Iranian Kurdish Patients from Kermanshah

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