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  • Matrix metalloproteinase-14 both sheds cell surface neuronal glial antigen 2 (NG2) proteoglycan on macrophages and governs the response to peripheral nerve injury.

Matrix metalloproteinase-14 both sheds cell surface neuronal glial antigen 2 (NG2) proteoglycan on macrophages and governs the response to peripheral nerve injury.

The Journal of biological chemistry (2014-12-10)
Tasuku Nishihara, Albert G Remacle, Mila Angert, Igor Shubayev, Sergey A Shiryaev, Huaqing Liu, Jennifer Dolkas, Andrei V Chernov, Alex Y Strongin, Veronica I Shubayev
RÉSUMÉ

Neuronal glial antigen 2 (NG2) is an integral membrane chondroitin sulfate proteoglycan expressed by vascular pericytes, macrophages (NG2-Mφ), and progenitor glia of the nervous system. Herein, we revealed that NG2 shedding and axonal growth, either independently or jointly, depended on the pericellular remodeling events executed by membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14). Using purified NG2 ectodomain constructs, individual MMPs, and primary NG2-Mφ cultures, we demonstrated for the first time that MMP-14 performed as an efficient and unconventional NG2 sheddase and that NG2-Mφ infiltrated into the damaged peripheral nervous system. We then characterized the spatiotemporal relationships among MMP-14, MMP-2, and tissue inhibitor of metalloproteinases-2 in sciatic nerve. Tissue inhibitor of metalloproteinases-2-free MMP-14 was observed in the primary Schwann cell cultures using the inhibitory hydroxamate warhead-based MP-3653 fluorescent reporter. In teased nerve fibers, MMP-14 translocated postinjury toward the nodes of Ranvier and its substrates, laminin and NG2. Inhibition of MMP-14 activity using the selective, function-blocking DX2400 human monoclonal antibody increased the levels of regeneration-associated factors, including laminin, growth-associated protein 43, and cAMP-dependent transcription factor 3, thereby promoting sensory axon regeneration after nerve crush. Concomitantly, DX2400 therapy attenuated mechanical hypersensitivity associated with nerve crush in rats. Together, our findings describe a new model in which MMP-14 proteolysis regulates the extracellular milieu and presents a novel therapeutic target in the damaged peripheral nervous system and neuropathic pain.

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Anti-laminine antibody produced in rabbit, 0.5 mg/mL, affinity isolated antibody, buffered aqueous solution
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Anticorps anti-GAP43 ("Growth associated protein-43"), Chemicon®, from rabbit
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Anti-MMP-2 Antibody, a.a. 468-483 hMMP2, clone 42-5D11, clone 42-5D11, Chemicon®, from mouse
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Anticorps anti-domaine catalytique de la MT1-MMP humaine, clone 3G4.2, clone 3G4.2, Chemicon®, from mouse
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