title: Matrix metalloproteinase-14 both sheds cell surface neuronal glial antigen 2 (NG2) proteoglycan on macrophages and governs the response to peripheral nerve injury.
abstract: 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.
authors.affiliation: From the Departments of Anesthesiology, University of California, San Diego, La Jolla, California 92093, Veterans Affairs San Diego Healthcare System, La Jolla, California 92037, Department of Anesthesiology and Resuscitology, Ehime University, Toon, Ehime 791-0295, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Nishihara
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037, and.
authors.forename: Albert G
authors.initials: AG
authors.lastname: Remacle
authors.affiliation: From the Departments of Anesthesiology, University of California, San Diego, La Jolla, California 92093, Veterans Affairs San Diego Healthcare System, La Jolla, California 92037.
authors.forename: Mila
authors.initials: M
authors.lastname: Angert
authors.affiliation: Veterans Affairs San Diego Healthcare System, La Jolla, California 92037.
authors.forename: Igor
authors.initials: I
authors.lastname: Shubayev
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037, and.
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Shiryaev
authors.affiliation: From the Departments of Anesthesiology, University of California, San Diego, La Jolla, California 92093, Veterans Affairs San Diego Healthcare System, La Jolla, California 92037.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Departments of Anesthesiology, University of California, San Diego, La Jolla, California 92093, Veterans Affairs San Diego Healthcare System, La Jolla, California 92037.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dolkas
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037, and.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Chernov
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California 92037, and.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
authors.affiliation: From the Departments of Anesthesiology, University of California, San Diego, La Jolla, California 92093, Veterans Affairs San Diego Healthcare System, La Jolla, California 92037, vshubayev@ucsd.edu.
authors.forename: Veronica I
authors.initials: VI
authors.lastname: Shubayev
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism*; D001369:Axons / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009416:Nerve Regeneration; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000503:physiopathology; D011509:Proteoglycans / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries / Q000502:physiology; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D019922:GAP-43 Protein; D007797:Laminin; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; C522363:Mmp2 protein, rat
keywords: Extracellular Matrix; MT1-MMP; Macrophage; Matrix Metalloproteinase (MMP); NG2; Nerve; Pain; Proteoglycan; Regeneration; Schwann Cells