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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Prophylactic inhibition of neutrophil elastase prevents the development of chronic neuropathic pain in osteoarthritic mice

Authors: Milind M. Muley, Eugene Krustev, Allison R. Reid, Jason J. McDougall

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

A subset of osteoarthritis (OA) patients experience joint pain with neuropathic characteristics. Mediators such as neutrophil elastase, a serine proteinase, may be released during acute OA inflammatory flares. We have previously shown that local administration of neutrophil elastase causes joint inflammation and pain via activation of proteinase-activated receptor-2 (PAR2). The aim of this study was to examine the contribution of endogenous neutrophil elastase and PAR2 to the development of joint inflammation, pain, and neuropathy associated with monoiodoacetate (MIA)-induced experimental OA.

Methods

MIA (0.3 mg/10 μl) was injected into the right knee joint of male C57BL/6 mice (20–34 g). Joint inflammation (edema, leukocyte kinetics), neutrophil elastase proteolytic activity, tactile allodynia, and saphenous nerve demyelination were assessed over 14 days post-injection. The effects of inhibiting neutrophil elastase during the early inflammatory phase of MIA (days 0 to 3) were determined using sivelestat (50 mg/kg i.p.) and serpinA1 (10 μg i.p.). Involvement of PAR2 in the development of MIA-induced joint inflammation and pain was studied using the PAR2 antagonist GB83 (5 μg i.p. days 0 to 1) and PAR2 knockout animals.

Results

MIA caused an increase in neutrophil elastase proteolytic activity on day 1 (P < 0.0001), but not on day 14. MIA also generated a transient inflammatory response which peaked on day 1 (P < 0.01) then subsided over the 2-week time course. Joint pain appeared on day 1 and persisted to day 14 (P < 0.0001). By day 14, the saphenous nerve showed signs of demyelination. Early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase on day 1 (P < 0.001), and caused lasting improvements in joint inflammation, pain, and saphenous nerve damage (P < 0.05). MIA-induced synovitis was reversed by early treatment with GB83 and attenuated in PAR2 knockout mice (P < 0.05). PAR2 knockout mice also showed reduced MIA-induced joint pain (P < 0.0001) and less nerve demyelination (P = 0.81 compared to saline control).

Conclusions

Neutrophil elastase and PAR2 contribute significantly to the development of joint inflammation, pain, and peripheral neuropathy associated with experimental OA, suggesting their potential as therapeutic targets.
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Metadata
Title
Prophylactic inhibition of neutrophil elastase prevents the development of chronic neuropathic pain in osteoarthritic mice
Authors
Milind M. Muley
Eugene Krustev
Allison R. Reid
Jason J. McDougall
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0944-0

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