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

J Biol Chem. 2015 Feb 6;290(6):3693-707. doi: 10.1074/jbc.M114.603431. Epub 2014 Dec 8.


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.

Keywords: Extracellular Matrix; MT1-MMP; Macrophage; Matrix Metalloproteinase (MMP); NG2; Nerve; Pain; Proteoglycan; Regeneration; Schwann Cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens / metabolism*
  • Axons / physiology
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Extracellular Space / metabolism
  • Female
  • GAP-43 Protein / genetics
  • GAP-43 Protein / metabolism
  • HEK293 Cells
  • Humans
  • Laminin / genetics
  • Laminin / metabolism
  • MCF-7 Cells
  • Macrophages / metabolism*
  • Male
  • Matrix Metalloproteinase 14 / metabolism*
  • Matrix Metalloproteinase 2 / metabolism
  • Nerve Regeneration
  • Peripheral Nerve Injuries / metabolism*
  • Peripheral Nerve Injuries / physiopathology
  • Proteoglycans / metabolism*
  • Proteolysis
  • Rats
  • Rats, Sprague-Dawley
  • Schwann Cells / metabolism
  • Sciatic Nerve / injuries
  • Sciatic Nerve / physiology


  • Antigens
  • GAP-43 Protein
  • Laminin
  • Proteoglycans
  • chondroitin sulfate proteoglycan 4
  • Matrix Metalloproteinase 2
  • Mmp2 protein, rat
  • Matrix Metalloproteinase 14