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

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

Brain, behavior, and immunity (2016-11-12)
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
초록

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.

MATERIALS
제품 번호
브랜드
제품 설명

Sigma-Aldrich
Anti-MMP-14 Antibody, serum, Chemicon®
Sigma-Aldrich
Anti-Human MT1-MMP catalytic domain Antibody, clone 3G4.2, clone 3G4.2, Chemicon®, from mouse
Sigma-Aldrich
Anti-MMP-2 Antibody, a.a. 468-483 hMMP2, clone 42-5D11, clone 42-5D11, Chemicon®, from mouse
Sigma-Aldrich
Anti-Myelin Basic Protein Antibody, serum, Chemicon®