Matrix Metalloproteinases and Their Inhibitors in the Developing Mouse Brain and Spinal Cord: A Reverse Transcription Quantitative Polymerase Chain Reaction Study

Ulrich, Reiner; Gerhauser, Ingo; Seeliger, Frank; Baumgärtner, Wolfgang; Alldinger, Susanne

doi:10.1159/000088455

Cited by 72 publications

(67 citation statements)

References 86 publications

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“…Using an RPA assay that allowed the simultaneous detection of nine MMP members, we show that MMP-9 and MMP-12 transcripts are selectively upregulated in the optic nerve at periods correlating with myelination; a correlation between the upregulation of MMP-12 transcript and myelination in the rhombencephalon and spinal cord of mice was recently reported (Ulrich et al, 2005). We found that the elevation of MMP-9 and -12 has functional roles, because there is deficient myelination in MMP-9 and -12 null mice from P7 to P14.…”

Section: Discussionmentioning

confidence: 66%

Myelin Formation during Development of the CNS Is Delayed in Matrix Metalloproteinase-9 and -12 Null Mice

Larsen

DaSilva

Conant³

et al. 2006

J. Neurosci.

121

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The matrix metalloproteinases (MMPs) are implicated in several activities within the nervous system. Although many functions of abnormally elevated MMPs are undesirable, the discrete expression of particular MMP members can have beneficial roles. We previously found that MMP-9 expressed locally around a demyelinating lesion of the spinal cord of adult mice facilitated remyelination. In the current study, we have addressed whether and how MMPs might be required for myelin formation in normal ontogeny. Using a probe for multiple MMPs and the developing mouse optic nerve, we found two members, MMP-9 and -12, to be upregulated during the period of myelin formation. These MMPs partake in myelinogenesis because myelination in the corpus callosum of MMP-9 and/or MMP-12 null mice was deficient from postnatal days 7 to 14 compared with that of wild-type mice. The deficient myelination was correlated with fewer mature oligodendrocytes, but similar precursor cell numbers, in MMP null animals compared with wild type. Because an important growth factor for oligodendrocyte maturation is insulin-like growth factor-1 (IGF-1), we addressed whether this was involved in the deficient myelination in MMP null mice. Indeed, the addition of IGF-1 normalized the lack of maturation of oligodendrocytes that occurred in cultures from MMP-12 null mice. Furthermore, we determined that IGF binding protein 6 (IGFBP-6), which sequesters IGF-1, was a substrate for MMP processing. Finally, we found IGFBP-6 levels to remain high in MMP-deficient mice. These results reveal a novel function for MMP-9 and -12 in developmental myelination likely through regulating IGF-1 bioavailability.

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Section: Discussionmentioning

confidence: 66%

Myelin Formation during Development of the CNS Is Delayed in Matrix Metalloproteinase-9 and -12 Null Mice

Larsen

DaSilva

Conant³

et al. 2006

J. Neurosci.

121

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“…Diseases of the nervous system. In the nervous system, relatively high mRNA and protein levels of MMP-14, MMP-15, and MMP-24 and TIMP-1 and TIMP-3 are found in the perinatal rodent central nervous system (CNS) but generally decline with age (Ayoub et al, 2005;Fager and Jaworski, 2000;Jaworski, 2000;Ranasinghe et al, 2009;Rivera et al, 1997;Ulrich et al, 2005;Vaillant et al, 1999).…”

Section: Tumorigenesismentioning

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

209

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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“…Maier et al 24 described that metalloproteinase activity was required for processing of the oligodendrocyte-specific isoform of neurofascin involved in the formation of the paranodal axo-glial junction. Ulrich et al 25 found MMP-12 transcripts to be expressed temporally with developmental myelination, and they noted that "MMP-12 might be decisive for myelination. "…”

Section: The Beneficial Functions Of the Mmps In The Cns In Developmementioning

confidence: 99%

Targeting MMPs in Acute and Chronic Neurological Conditions

2007

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Summary:The matrix metalloproteinases (MMPs) are important enzymes that regulate developmental processes, maintain normal physiology in adulthood and have reparative roles at specific stages after an insult to the nervous system. Conversely, the concordant presence and significant upregulation of several MMP members in virtually all neurological conditions result in pathology. Thus, the MMPs have diverse functions, capable of mediating repair and recovery on the one hand and being involved in producing injury on the other. Therefore, targeting MMPs in neurological conditions has become a complicated challenge. This article highlights the beneficial roles of MMPs in normal and reparative processes within the nervous system and discusses the detriments of MMPs encountered in pathology. We review the availability of MMP inhibitors for clinical use and propose that an important consideration for these inhibitors is timing and duration of their use. With acute injuries where a massive upregulation of several MMPs are observed in the early periods after the insult, early and short-term use of broad spectrum MMP inhibitors would seem logical. In chronic conditions where recurrent insults to the CNS are accompanied by prolonged upregulation of MMPs, thereby necessitating the chronic use of medications, the beneficial effects of MMPs in repair may be compromised by the long-term application of MMP inhibitors. In this review we have used spinal cord injury and multiple sclerosis as examples of acute and chronic neurological conditions, respectively, and we consider the use of MMP inhibitors in these states.

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Matrix Metalloproteinases and Their Inhibitors in the Developing Mouse Brain and Spinal Cord: A Reverse Transcription Quantitative Polymerase Chain Reaction Study

Cited by 72 publications

References 86 publications

Myelin Formation during Development of the CNS Is Delayed in Matrix Metalloproteinase-9 and -12 Null Mice

Myelin Formation during Development of the CNS Is Delayed in Matrix Metalloproteinase-9 and -12 Null Mice

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

Targeting MMPs in Acute and Chronic Neurological Conditions

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