MMP‐2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP‐9 expression and activity

Esparza, Jordi; Kruse, Meghan; Lee, Janet Y.; Michaud, Michael; Madri, Joseph A.

doi:10.1096/fj.04-2445com

Cited by 94 publications

(85 citation statements)

References 40 publications

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“…Purified Hsp70 has been shown to act as a novel cytokine, which causes monocytes to express proinflammatory cytokines such as IL-1, IL-6, and TNF- (Asea et al, 2000;Esparza et al, 2004). However, other reports suggested that Hsp70-mediated induction of proinflammatory cytokines might be due to contamination by LPS as well as LPS-associated molecules (Gao and Tsan, 2003a, b).…”

Section: Discussionmentioning

confidence: 99%

“…There are a number of reports on the secretion of Hsp70 independent of necrotic cell death (Hightower et al, 1989;Broquet et al, 2003;Esparza et al, 2004;Hunter-Lavis et al, 2004;Adewoye et al, 2005;Dybdahl et al, 2005;Svensson et al, 2005). To explore whether Hsp70 could be released from Hsp70 transfectants to the culture medium, Hsp70 and mock transfectants were cultured in the absence or presence of PMA, and the amount of Hsp70 released in the culture medium was then measured by Western blot analysis.…”

Section: Hsp70 Is Secreted From the Cells To Culture Supernatants Anmentioning

confidence: 99%

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Release of heat shock protein 70 (Hsp70) and the effects of extracellular Hsp70 on matric metalloproteinase-9 expression in human monocytic U937 cells

Lee

Kim²,

Kim³

et al. 2006

Exp Mol Med

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Heat shock protein 70 (Hsp70) release and its effects on pro-inflammatory cytokine production have been controversial. In this study, we investigated whether Hsp70 could be released from monocytes and activates matrix metalloproteinase-9 (MMP-9) gene expression. Hsp70 overexpression in human monocytic cell line U937 was found to increase PMAinduced MMP-9 expression and enhance cell motility. Hsp70 cDNA transfectants released Hsp70 protein into culture supernatants, and a part of released Hsp70 subsequently was bound to the surface of U937 cells. Addition of culture medium containing the extracelluar Hsp70 led to an increase not only in proMMP-9 secretion, but also the invasiveness of U937 cells through Matrigel or human umbilical vascular endothelial cells (HUVEC) in vitro. Immunodepletion of Hsp70 abolished its effect on MMP-9 expression. The released Hsp70 activated nuclear factor kappa B (NF-κB) and activating protein-1 (AP-1), which led to the activation of MMP-9 transcription. Taken together, these results suggest that extracellular Hsp70 induces the expression of MMP-9 gene through activation of NF-κB and AP-1.

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Section: Discussionmentioning

confidence: 99%

Section: Hsp70 Is Secreted From the Cells To Culture Supernatants Anmentioning

confidence: 99%

Release of heat shock protein 70 (Hsp70) and the effects of extracellular Hsp70 on matric metalloproteinase-9 expression in human monocytic U937 cells

Lee

Kim²,

Kim³

et al. 2006

Exp Mol Med

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“…Current data indicate that MMP12 contributes to emphysema 113,114 , whereas MMP3 and MMP9 contribute to skin inflammatory conditions 89,115 . By contrast, MMP8 protects against skin inflammatory responses 104 and MMP2 protects against inflammation of the brain and spinal cord 116 . Collectively, these observations indicate that MMPs function non-redundantly to regulate inflammation, which is potentially of great medical significance.…”

Section: Mmps In Human Inflammatory Disease Modelsmentioning

confidence: 98%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,560

2,180

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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“…In this study, we show anomalous MMP-9 upregulation in the spinal cord-injured MMP-2 null animal. Similarly, MMP-9 is upregulated in a model of experimental autoimmune encephalomyelitis in MMP-2 null mice (Esparza et al, 2004). As a consequence of compensatory MMP-9 upregulation in lymphocytes and endothelial cells, MMP-2 null mice display an early onset of the disease with a worsened outcome.…”

Section: Glial Scar Formation and Mmp-2mentioning

confidence: 99%

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

Hsu¹,

McKeon²,

Goussev³

et al. 2006

J. Neurosci.

205

184

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Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in both injury and repair mechanisms in the CNS. Pharmacological blockade of MMPs, limited to the first several days after spinal cord injury, improves locomotor recovery. This beneficial response is, however, lost when treatment is extended beyond the acutely injured cord to include wound healing and tissue remodeling. This suggests that some MMPs play a beneficial role in wound healing. To test this hypothesis, we investigated the role of MMP-2, which is actively expressed during wound healing, in white matter sparing and axonal plasticity, the formation of a glial scar, and locomotor recovery after spinal cord injury. MMP-2 increased between 7 and 14 d after injury, where it was immunolocalized in reactive astrocytes bordering the lesion epicenter. There was reduced white matter sparing and fewer serotonergic fibers, caudal to the lesion in injured MMP-2 null animals. MMP-2 deficiency also resulted in increased immunoreactivity to chondroitin sulfate proteoglycans and a more extensive astrocytic scar. Most importantly, locomotion in an open field, performance on a rotarod, and grid walking were significantly impaired in injured MMP-2 null mice. Our findings suggest that MMP-2 promotes functional recovery after injury by regulating the formation of a glial scar and white matter sparing and/or axonal plasticity. Thus, strategies exploiting MMPs as therapeutic targets must balance these beneficial effects during wound healing with their adverse interactions in the acutely injured spinal cord.

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MMP‐2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP‐9 expression and activity

Cited by 94 publications

References 40 publications

Release of heat shock protein 70 (Hsp70) and the effects of extracellular Hsp70 on matric metalloproteinase-9 expression in human monocytic U937 cells

Release of heat shock protein 70 (Hsp70) and the effects of extracellular Hsp70 on matric metalloproteinase-9 expression in human monocytic U937 cells

Matrix metalloproteinases and the regulation of tissue remodelling

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

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