Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain

Sanghyun Hong, Albert G. Remacle, Sergei A. Shiryaev, Wonjun Choi, Swathi K. Hullugundi, Jennifer Dolkas, Mila Angert, Tasuku Nishihara, Tony L. Yaksh, Alex Y. Strongin, Veronica I. Shubayev

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Myelin basic protein (MBP) is an auto-antigen able to induce intractable pain from innocuous mechanical stimulation (mechanical allodynia). The mechanisms provoking this algesic MBP activity remain obscure. Our present study demonstrates that membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) releases the algesic MBP peptides from the damaged myelin, which then reciprocally enhance the expression of MT1-MMP in nerve to sustain a state of allodynia. Specifically, MT1-MMP expression and activity in rat sciatic nerve gradually increased starting at day 3 after chronic constriction injury (CCI). Inhibition of the MT1-MMP activity by intraneural injection of the function-blocking human DX2400 monoclonal antibody at day 3 post-CCI reduced mechanical allodynia and neuropathological signs of Wallerian degeneration, including axon demyelination, degeneration, edema and formation of myelin ovoids. Consistent with its role in allodynia, the MT1-MMP proteolysis of MBP generated the MBP69-86-containing epitope sequences in vitro. In agreement, the DX2400 therapy reduced the release of the MBP69-86 epitope in CCI nerve. Finally, intraneural injection of the algesic MBP69-86 and control MBP2-18 peptides differentially induced MT1-MMP and MMP-2 expression in the nerve. With these data we offer a novel, self-sustaining mechanism of persistent allodynia via the positive feedback loop between MT1-MMP and the algesic MBP peptides. Accordingly, short-term inhibition of MT1-MMP activity presents a feasible pharmacological approach to intervene in this molecular circuit and the development of neuropathic pain.

Original languageEnglish
Pages (from-to)282-292
Number of pages11
JournalBrain, Behavior, and Immunity
Volume60
DOIs
StatePublished - 1 Feb 2017

Bibliographical note

Publisher Copyright:
© 2016

Keywords

  • Allodynia
  • MBP
  • MMP
  • Myelin
  • Neuropathic pain
  • Peripheral nerve

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