Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Milward, Elizabeth A.; Kim, Kee Jun; Szklarczyk, Arek; Nguyen, Thien; Melli, Giorgia; Nayak, Mamatha S.; Deshpande, Deepa; Fitzsimmons, Chantel; Höke, Ahmet; Kerr, Douglas A.; Griffin, John W.; Calabresi, Peter A.; Conant, Katherine

doi:10.1016/j.jneuroim.2007.11.001

Cited by 42 publications

(44 citation statements)

References 66 publications

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“…The present study provides the first evidence that LPA down-regulates MAG protein expression in the DR in a calpaindependent manner, using in vivo and ex vivo experiments. While MMP is reported to degrade MAG as well as MBP (Gijbels et al 1993, D'Souza & Moscarello 2006, Milward et al 2008, LPA-induced down-regulation of MAG was insensitive to the MMP inhibitor. Moreover, we found that LPA markedly induces calpain activity in the DR, using a fluorometric assay.…”

Section: Discussionmentioning

confidence: 96%

Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain

Xie

Uchida

Nagai

et al. 2010

Journal of Neurochemistry

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Lysophosphatidic acid receptor (LPA 1 ) signaling initiates neuropathic pain through demyelination of the dorsal root (DR). Although LPA is found to cause down-regulation of myelin proteins underlying demyelination, the detailed mechanism remains to be determined. In the present study, we found that a single intrathecal (i.t.) injection of LPA evoked a dose-and time-dependent downregulation of myelin-associated glycoprotein (MAG) in the DR through LPA 1 receptor. A similar event was also observed in ex vivo DR cultures. Interestingly, LPA-induced down-regulation of MAG was significantly inhibited by calpain inhibitors (calpain inhibitor X, E-64 and E-64d) and LPA markedly induced calpain activation in the DR. The pre-treatment with calpain inhibitors attenuated LPA-induced neuropathic pain behaviors such as hyperalgesia and allodynia. Moreover, we found that sciatic nerve injury activates calpain activity in the DR in a LPA 1 receptor-dependent manner. The E-64d treatments significantly blocked nerve injury-induced MAG down-regulation and neuropathic pain. However, there was no significant calpain activation in the DR by complete Freund's adjuvant treatment, and E-64d failed to show anti-hyperalgesic effects in this inflammation model. The present study provides strong evidence that LPA-induced calpain activation plays a crucial role in the manifestation of neuropathic pain through MAG down-regulation in the DR. Keywords lysophosphatidic acid; neuropathic pain; myelin-associated glycoprotein; dorsal root; calpain; demyelination Lysophosphatidic acid (LPA) is a bioactive lipid mediator that exerts diverse physiological and pathophysiological functions through its cognate LPA receptors (LPA 1-5 and P2Y5) (Noguchi et al. 2009). Recently, we demonstrated that LPA 1 receptor signaling initiates neuropathic pain following peripheral nerve injury, using mice lacking the lpa 1 gene (Lpar1 −/− ) (Inoue et al. 2004, Ueda 2008. Regarding the molecular bases, LPA upregulates pain-related gene expression, such as Ca 2+ channel α2δ-1 subunit and ephrinB1 in the dorsal root ganglion (DRG) and protein kinase C γ-isoform in the spinal cord (Inoue et al. 2004, Uchida et al. 2009). Moreover, LPA causes demyelination of the dorsal root (DR) * Correspondence to: Dr. Hiroshi Ueda, Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan, Tel: +81-95-819-2421; Fax: +81-95-819-2420; ueda@nagasaki-u.ac.jp. † These authors contributed equally to this study. NIH Public Access Materials and methods Animals and surgeryMale mice lacking the lpa 1 gene (Lpar1 −/− ) (Contos et al. 2000) and wild type C57BL/6J mice weighing 20-24 g were used. They were kept in a room with a temperature of 21 ± 2°C with free access to standard laboratory diet and tap water. All procedures were approved by the Nagasaki University Animal Care Committee and complied with the recommendations of the International Association for the Study of Pain (Zimmermann 1...

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Section: Discussionmentioning

confidence: 96%

Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain

Xie

Uchida

Nagai

et al. 2010

Journal of Neurochemistry

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“…About this last aspect, two proteins have been identified as the main source of auto-immunoreactivity: the small heat shock protein a-B crystallin and the myelin basic protein. They are both degraded by MMP-9 (Shiryaev et al, 2009a;Van Noort and Amor, 1998) and fragments share the immunogenic property (Milward et al, 2008;Shiryaev et al, 2009a). Additionally, the therapeutical administration of not-glycosylated interferon-b has been demonstrated to be detrimental for disease outcome, since the MMP-9 dependent cleavage of that cytokine form, initially adopted in clinical trials, has been shown to be a further source of auto-antibodies .…”

Section: 242mentioning

confidence: 99%

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Sbardella

Fasciglione

Gioia

et al. 2012

Molecular Aspects of Medicine

205

212

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a b s t r a c tHuman matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn 2+ atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes.

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“…In animal models of immune-mediated, demyelinating diseases, it has been demonstrated that gelatinases (MMP-2 and MMP-9) are critically involved in the process of inflammation by disrupting the blood nerve barrier and promoting cell injury (Kieseier et al, 1998a(Kieseier et al, , 1999. However, in a regenerative milieu, MMP-2 and MMP-9 are known to facilitate repair mechanisms by promoting cell differentiation, axonal growth and guidance (Krekoski et al, 2002;Vaillant et al, 2003), and remodelling of the extracellular matrix (Heine et al, 2004;Milward et al, 2008). Although MMP-9 is usually undetectable in normal peripheral nerve tissue, MMP-2 is expressed by Schwann cells and upregulated after nerve injury (Krekoski et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Matrix metalloproteinase‐2 is involved in myelination of dorsal root ganglia neurons

Lehmann¹,

Köhne²,

Bernal³

et al. 2008

Glia

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Matrix metalloproteinases (MMPs) comprise a large family of endopeptidases that are capable of degrading all extracellular matrix components. There is increasing evidence that MMPs are not only involved in tissue destruction but may also exert beneficial effects during axonal regeneration and nerve remyelination. Here, we provide evidence that MMP-2 (gelatinase A) is associated with the physiological process of myelination in the peripheral nervous system (PNS). In a myelinating co-culture model of Schwann cells and dorsal root ganglia neurons, MMP-2 expression correlated with the degree of myelination as determined by immunocytochemistry, zymography, and immunosorbent assay. Modulation of MMP-2 activity by chemical inhibitors led to incomplete and aberrant myelin formation. In vivo MMP-2 expression was detected in the cerebrospinal fluid (CSF) of patients with Guillain-Barré syndrome as well as in CSF and sural nerve biopsies of patients with chronic inflammatory demyelinating polyneuropathy. Our findings suggest an important, previously unrecognized role for MMP-2 during myelination in the PNS. Endogenous or exogenous modulation of MMP-2 activity may be a relevant target to enhance regeneration in demyelinating diseases of the PNS.

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Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Cited by 42 publications

References 66 publications

Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain

Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Matrix metalloproteinase‐2 is involved in myelination of dorsal root ganglia neurons

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