Matrix metalloproteinase-14 both sheds cell surface NG2 proteoglycan on macrophages and governs the response to peripheral nerve injury [Neurobiology]

December 8th, 2014 by Nishihara, T., Remacle, A. G., Angert, M., Shubayev, I., Shiryaev, S. A., Liu, H., Dolkas, J., Chernov, A. V., Strongin, A. Y., Shubayev, V. I.

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 PNS. We then characterized the spatio-temporal relationships among MMP-14, MMP-2, and TIMP-2 (tissue inhibitor of metalloproteinases-2) in sciatic nerve. TIMP-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 post-injury towards 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, GAP-43 and ATF3, 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 PNS and neuropathic pain.
  • Posted in Journal of Biological Chemistry, Publications
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