Matrix metalloproteinase‐3 in the central nervous system: a look on the bright side

Abstract

Matrix metalloproteinases (MMPs) are a large family of proteases involved in many cell-matrix and cell-cell signalling processes through activation, inactivation or release of extracellular matrix (ECM) and non-ECM molecules, such as growth factors and receptors. Uncontrolled MMP activities underlie the pathophysiology of many disorders. Also matrix metalloproteinase-3 (MMP-3) or stromelysin-1 contributes to several pathologies, such as cancer, asthma and rheumatoid arthritis, and has also been associated with neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and multiple sclerosis. However, based on defined MMP spatiotemporal expression patterns, the identification of novel candidate molecular targets and in vitro and in vivo studies, a beneficial role for MMPs in CNS physiology and recovery is emerging. The main purpose of this review is to shed light on the recently identified roles of MMP-3 in normal brain development and in plasticity and regeneration after CNS injury and disease. As such, MMP-3 is correlated with neuronal migration and neurite outgrowth and guidance in the developing CNS and contributes to synaptic plasticity and learning in the adult CNS. Moreover, a strict spatiotemporal MMP-3 up-regulation in the injured or diseased CNS might support remyelination and neuroprotection, as well as genesis and migration of stem cells in the damaged brain. Keywords: central nervous system, development, matrix metalloproteinase-3, plasticity, regeneration, repair. Matrix metalloproteinases: an overviewMatrix metalloproteinases (MMPs) are proteolytic enzymes that remodel the pericellular environment by degrading all protein constituents of the extracellular matrix (ECM). Besides, they also regulate many cell signalling pathways and homeostatic systems by cleavage and release of various guidance and adhesion molecules, receptors, growth factors, cytokines, etc., through either activation or inactivation. The MMP family, a subgroup of the metzincins, constitutes more than 20 mammalian members, which are all Zn 2+ -dependent endopeptidases. Based on their substrate specificity and domain organization, MMPs are classified into collagenases, gelatinases, stromelysins, membrane-type MMPs, matrilysins and 'other MMPs' (Nagase et al. 2006).MMP activities are kept under tight control. First of all, MMP expression can be regulated at the transcriptional level by growth factors, cytokines, chemokines, hormones, epigenetic processes and cell-cell/cell-ECM interactions. Membrane-trafficking and subsequent release of MMPs at the cell surface can be regulated by SNARE proteins (Kean et al. 2009). MMPs are synthesized as proenzymes with a 'cysteine switch', the disruption of the interaction between the cysteine residue in the propeptide and the Zn 2+ ion in the catalytic site, as a pre-requisite for activation. This disruption can be achieved by organomercurial compounds, heavy metals, denaturating agents or oxidants, as well as through removal of the propeptide by proteases (Van Wart and Birk...

Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases

“…The fact that PCLDs may progress through processes of survival, neovascularisation and loss of cell adhesion1–3 10 prompted us to study in vivo the expression of MMP-3, a metalloprotease reported to participate in all of these mechanisms 18. MMP-3 was found to be ∼4.5-fold and ∼35-fold overexpressed in polycystic human and rat cholangiocyte cultures, respectively (p < 0.0001; figure 1B and see online supplementary figure S3B), and is stimulated by both IL-8 and 17β-oestradiol in normal human cholangiocytes (see online supplementary figure S4B and S4D, respectively).…”

The Significance of Matrix Metalloproteinases in the Immunopathogenesis and Treatment of Multiple Sclerosis = أهمية الأنزيمات المعدنية المحللة للبروتين في تطور مرض التصلب العصبي المتعدد و علاجه

“…53 Interestingly, it has been reported that MMP-3 can be involved in normal CNS-remodelling and in the remyelination process, as shown by the strict spatiotemporal MMP-3 upregulation in the injured CNS, which may contribute to stem cell migration, neuroprotection and remyelination in the injured sites. 51 An involvement of MMP-3 in remyelination during the regenerative period after a CNS injury was demonstrated for the first time in the murine cuprizone-induced demyelination model. It was reported that not only during the early demyelination stage, but also during the stage of remyelination, MMP-3 was highly expressed in astrocytes of the corpus callosum.…”

“…50 It has been demonstrated that MMP-3 contributes to different pathological conditions, such as rheumatoid arthritis (RA), asthma, cancer and neurological disorders, including MS, Parkinson's disease (PD) and Alzheimer's disease (AD). 51 In MS, the increased circulatory level of MMP-3 correlates with disease activity in RRMS. This may contribute to the breakdown of the BBB at the time of relapse.…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…study of cultured mouse NG2 glia exposed to Il17 or Tnf [158] Neuronal and synaptic plasticity [159] Matrix Metalloprotease 9, MMP9…”