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Monoclonal Antibody Targeting the Matrix Metalloproteinase 9 Prevents and Reverses Paclitaxel-Induced Peripheral Neuropathy in Mice

  • Raquel Tonello
    Affiliations
    Department of Anesthesiology, Pain Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
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  • Sang Hoon Lee
    Affiliations
    Department of Anesthesiology, Pain Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
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  • Temugin Berta
    Correspondence
    Address reprint requests to Temugin Berta, PhD, Pain Research Center, Department of Anesthesiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0531, Cincinnati, OH 45267-0531.
    Affiliations
    Department of Anesthesiology, Pain Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
    Search for articles by this author
Published:November 21, 2018DOI:https://doi.org/10.1016/j.jpain.2018.11.003

      Highlights

      • CINP in mice is associated with transcriptional changes in MMP signaling.
      • MMP9 expression is increased in small-sized DRG neurons after paclitaxel.
      • MMP9 antibody prevents paclitaxel-induced oxidative stress and neuroinflammation.
      • MMP9 antibody alleviates paclitaxel-induced mechanical allodynia in mice.

      Abstract

      Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling condition accompanying several cancer drugs, including the front-line chemotherapeutic agent paclitaxel. Although CIPN can force dose reduction or even discontinuation of chemotherapy, affecting survival in cancer patients, there is no US Food and Drug Administration–approved treatment for CIPN. CIPN in mice is characterized by neuropathic pain (eg, mechanical allodynia) in association with oxidative stress and neuroinflammation in dorsal root ganglia (DRGs), as well as retraction of intraepidermal nerve fibers. Here, we report that paclitaxel-induced mechanical allodynia is associated with transcriptional increase in matrix metalloproteinase (MMP) 2 and 9 and decrease in metallopeptidase inhibitor 1 (TIMP1), a strong endogenous MMP9 inhibitor. Consistently, MMP9 protein levels are increased in DRG neurons in vivo and in vitro after paclitaxel treatment, and it is demonstrated, for the first time, that intrathecal injections of exogenous TIMP1 or a monoclonal antibody targeting MMP9 (MMP9 mAb) significantly prevented and reversed paclitaxel-induced mechanical allodynia in male and female mice. Analyses of DRG tissues showed that MMP9 mAb significantly decreased oxidative stress and neuroinflammatory mediators interleukin-6 and tumor necrosis factor α, as well as prevented paclitaxel-induced loss of intraepidermal nerve fibers. These findings suggest that MMP signaling plays a key role in paclitaxel-induced peripheral neuropathy, and MMP9 mAb may offer new therapeutic approaches for the treatment of CIPN.

      Perspective

      Chemotherapy-induced peripheral neuropathy (CIPN) remains ineffectively managed in cancer patients, potentially leading to the discontinuation of an otherwise life-saving treatment. Here, we demonstrate that a monoclonal antibody targeting MMP9 alleviates neuropathic pain and several mechanisms linked to CIPN. This study is particularly relevant, because a humanized MMP9 antibody is already in advanced clinical trials for the treatment of colitis and cancer, and it may be straightforwardly repurposed for the relief of CIPN.

      Key words

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      References

        • Amar S
        • Fields GB
        Potential clinical implications of recent matrix metalloproteinase inhibitor design strategies.
        Expert Rev Proteomics Informa Healthcare. 2015; 12: 445-447
        • Bennett GJ
        • Liu GK
        • Xiao WH
        • Jin HW
        • Siau C
        Terminal arbor degeneration—A novel lesion produced by the antineoplastic agent paclitaxel.
        Eur J Neurosci. 2011; 33: 1667-1676
        • Berta T
        • Liu T
        • Liu Y-C
        • Xu Z-Z
        • Ji R-R
        Acute morphine activates satellite glial cells and up-regulates IL-1β in dorsal root ganglia in mice via matrix metalloprotease-9.
        Mol Pain. 2012; 8: 18
        • Berta T
        • Perrin FE
        • Pertin M
        • Tonello R
        • Liu Y-C
        • Chamessian A
        • Kato AC
        • Ji R-R
        • Decosterd I
        Gene expression profiling of cutaneous injured and non-injured nociceptors in SNI animal model of neuropathic pain.
        Sci Rep. 2017; 7: 9367
        • Bouet V
        • Boulouard M
        • Toutain J
        • Divoux D
        • Bernaudin M
        • Schumann-Bard P
        • Freret T
        The adhesive removal test: A sensitive method to assess sensorimotor deficits in mice.
        Nat Protoc. 2009; 4: 1560-1564
        • Boyette-Davis J
        • Xin W
        • Zhang H
        • Dougherty PM
        Intraepidermal nerve fiber loss corresponds to the development of Taxol-induced hyperalgesia and can be prevented by treatment with minocycline.
        Pain. 2011; 152: 308-313
        • Boyette-Davis JA
        • Walters ET
        • Dougherty PM
        Mechanisms involved in the development of chemotherapy-induced neuropathy.
        Pain Manag. 2015; 5: 285-296
        • Bozdagi O
        • Nagy V
        • Kwei KT
        • Huntley GW
        In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity.
        J Neurophysiol. 2007; 98: 334-344
        • Brew K
        • Nagase H
        The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity.
        Biochim Biophys Acta Mol Cell Res. 2010; 1803: 55-71
      1. Brenner DS, Golden JP, Gereau IV RW: A novel behavioral assay for measuring cold sensation in mice. PLoS One 7, 2012.

        • Carozzi VA
        • Canta A
        • Chiorazzi A
        Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms?.
        Neurosci Lett. 2015; 596: 90-107
        • Cascella M
        Chemotherapy-induced peripheral neuropathy: limitations in current prophylactic strategies and directions for future research.
        Curr Med Res Opin. 2017; 33: 981-984
        • Chan AC
        • Carter PJ
        Therapeutic antibodies for autoimmunity and inflammation.
        Nat Rev Immunol. 2010; 10: 301-316
        • Chaplan SR
        • Bach FW
        • Pogrel JW
        • Chung JM
        • Yaksh TL
        Quantitative assessment of tactile allodynia in the rat paw.
        J Neurosci Methods. 1994; 53: 55-63
        • Costigan M
        • Befort K
        • Karchewski L
        • Griffin RS
        • D'Urso D
        • Allchorne A
        • Sitarski J
        • Mannion JW
        • Pratt RE
        • Woolf CJ
        Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury.
        BMC Neurosci. 2002; 3: 16
        • Dixon WJ
        Efficient analysis of experimental observations.
        Annu Rev Pharmacol Toxicol. 1980; 20: 441-462
        • Doyle T
        • Chen Z
        • Muscoli C
        • Bryant L
        • Esposito E
        • Cuzzocrea S
        • Dagostino C
        • Ryerse J
        • Rausaria S
        • Kamadulski A
        • Neumann WL
        • Salvemini D
        Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain.
        J Neurosci. 2012; 32: 6149-6160
        • Duggett NA
        • Griffiths LA
        • McKenna OE
        • de Santis V
        • Yongsanguanchai N
        • Mokori EB
        • Flatters SJL
        Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy.
        Neuroscience. 2016; 333: 13-26
        • Fidanboylu M
        • Griffiths LA
        • Flatters SJL
        Global inhibition of reactive oxygen species (ROS) inhibits paclitaxel-induced painful peripheral neuropathy.
        PLoS One. 2011; 6: e25212
        • Flatters SJL
        • Dougherty PM
        • Colvin LA
        Clinical and preclinical perspectives on chemotherapy-induced peripheral neuropathy (CIPN): A narrative review.
        Br J Anaesth. 2017; 119: 737-749
        • Flatters SJL
        • Xiao WH
        • Bennett GJ
        Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy.
        Neurosci Lett. 2006; 397: 219-223
        • Gong Y
        • Hart E
        • Shchurin A
        • Hoover-Plow J
        Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice.
        J Clin Invest. 2008; 118: 3012-3024
        • Grace PM
        • Gaudet AD
        • Staikopoulos V
        • Maier SF
        • Hutchinson MR
        • Salvemini D
        • Watkins LR
        Nitroxidative signaling mechanisms in pathological pain.
        Trends Neurosci. 2016; 39: 862-879
        • Holland NR
        • Crawford TO
        • Hauer P
        • Cornblath DR
        • Griffin JW
        • McArthur JC
        Small-fiber sensory neuropathies: Clinical course and neuropathology of idiopathic cases.
        Ann Neurol. 1998; 44: 47-59
        • Hylden JL
        • Wilcox GL
        Intrathecal morphine in mice: A new technique.
        Eur J Pharmacol. 1980; 67: 313-316
        • Barnham KJ
        • Masters CL
        • Bush AI
        Neurodegenerative diseases and oxidative stress.
        Nat Rev Drug Discov. 2004; 3: 39-46
        • Jackson HW
        • Defamie V
        • Waterhouse P
        • Khokha R
        TIMPs: Versatile extracellular regulators in cancer.
        Nat Rev Cancer. 2016; 17: 38-53
        • Ji R-R
        • Xu Z-Z
        • Gao Y-J
        Emerging targets in neuroinflammation-driven chronic pain.
        Nat Rev Drug Discov. 2014; 13: 533-548
        • Ji R-RR
        • Xu Z-ZZ
        • Wang X
        • Lo EH
        Matrix metalloprotease regulation of neuropathic pain.
        Trends Pharmacol Sci. 2009; 30: 336-340
        • Jiang L
        • Pan CL
        • Wang CY
        • Liu BQ
        • Han Y
        • Hu L
        • Liu L
        • Yang Y
        • Qu JW
        • Liu WT
        Selective suppression of the JNK-MMP2/9 signal pathway by tetramethylpyrazine attenuates neuropathic pain in rats.
        J Neuroinflammation. 2017; 14: 174
        • Kalliomäki M
        • Kieseritzky Jv
        • Schmidt R
        • Hägglöf B
        • Karlsten R
        • Sjögren N
        • Albrecht P
        • Gee L
        • Rice F
        • Wiig M
        • Schmelz M
        • Gordh T
        Structural and functional differences between neuropathy with and without pain?.
        Exp Neurol. 2011; 231: 199-206
        • Kawagishi H
        • Finkel T
        Unraveling the truth about antioxidants: ROS and disease: Finding the right balance.
        Nat Med. 2014; 20: 711-713
        • Kawasaki Y
        • Xu Z-Z
        • Wang X
        • Park JY
        • Zhuang Z-Y
        • Tan P-H
        • Gao Y-J
        • Roy K
        • Corfas G
        • Lo EH
        • Ji R-R
        Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain.
        Nat Med. 2008; 14: 331-336
        • Kelly PJ
        • Morrow JD
        • Ning MM
        • Koroshetz W
        • Lo EH
        • Terry E
        • Milne GL
        • Hubbard J
        • Lee H
        • Stevenson E
        • Lederer M
        • Furie KL
        Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study.
        Stroke. 2008; 39: 100-104
        • Khokha R
        • Murthy A
        • Weiss A
        Metalloproteinases and their natural inhibitors in inflammation and immunity.
        Nat Rev Immunol. 2013; 13: 649-665
        • Krukowski K
        • Eijkelkamp N
        • Laumet G
        • Hack CE
        • Li Y
        • Dougherty PM
        • Heijnen CJ
        • Kavelaars A
        CD8+ T cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain.
        J Neurosci. 2016; 36: 11074-11083
        • Ledeboer A
        • Jekich BM
        • Sloane EM
        • Mahoney JH
        • Langer SJ
        • Milligan ED
        • Martin D
        • Maier SF
        • Johnson KW
        • Leinwand LA
        • Chavez RA
        • Watkins LR
        Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats.
        Brain Behav Immun. 2007; 21: 686-698
        • Lee YH
        • Lai CL
        • Hsieh SH
        • Shieh CC
        • Huang LM
        • Wu-Hsieh BA
        Influenza A virus induction of oxidative stress and MMP-9 is associated with severe lung pathology in a mouse model.
        Virus Res. 2013; 178: 411-422
        • Li J
        • Xu L
        • Deng X
        • Jiang C
        • Pan C
        • Chen L
        • Han Y
        • Dai W
        • Hu L
        • Zhang G
        • Cheng Z
        • Liu W
        N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases.
        Pain. 2016; 157: 1711-1723
        • Li Y
        • Adamek P
        • Zhang H
        • Tatsui CE
        • Rhines LD
        • Mrozkova P
        • Li Q
        • Kosturakis AK
        • Cassidy RM
        • Harrison DS
        • Cata JP
        • Sapire K
        • Zhang H
        • Kennamer-Chapman RM
        • Jawad AB
        • Ghetti A
        • Yan J
        • Palecek J
        • Dougherty PM
        The cancer chemotherapeutic paclitaxel increases human and rodent sensory neuron responses to TRPV1 by activation of TLR4.
        J Neurosci. 2015; 35: 13487-13500
        • Lin MT
        • Beal MF
        Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.
        Nature. 2006; 443: 787-795
        • Liu CC
        • Lu N
        • Cui Y
        • Yang T
        • Zhao ZQ
        • Xin WJ
        • Liu XG
        Prevention of Paclitaxel-induced allodynia by Minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats.
        Mol Pain. 2010; 6: 76
        • Liu XJ
        • Zhang YL
        • Liu T
        • Xu ZZ
        • Park CK
        • Berta T
        • Jiang DH
        • Ji RR
        Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter.
        Cell Res. 2014; 24: 1374-1377
        • Liu Y-C
        • Berta T
        • Liu T
        • Tan P-H
        • Ji R-R
        Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice.
        Mol Pain. 2012; 8: 19
      2. Ma J, Kavelaars A, Dougherty PM, Heijnen CJ: Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: Targeting the source. Cancer 124:2289-2298, 2018

        • Makker PGS
        • Duffy SS
        • Lees JG
        • Perera CJ
        • Tonkin RS
        • Butovsky O
        • Park SB
        • Goldstein D
        • Moalem-Taylor G
        Characterisation of immune and neuroinflammatory changes associated with chemotherapy-induced peripheral neuropathy.
        PLoS One. 2017; 12e0170814
        • Mao-Ying QL
        • Kavelaars A
        • Krukowski K
        • Huo XJ
        • Zhou W
        • Price TJ
        • Cleeland C
        • Heijnen CJ
        The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.
        PLoS One. 2014; 9e100701
        • Marshall DC
        • Lyman SK
        • McCauley S
        • Kovalenko M
        • Spangler R
        • Liu C
        • Lee M
        • O'Sullivan C
        • Barry-Hamilton V
        • Ghermazien H
        • Mikels-Vigdal A
        • Garcia CA
        • Jorgensen B
        • Velayo AC
        • Wang R
        • Adamkewicz JI
        • Smith V
        Selective allosteric inhibition of MMP9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer.
        PLoS One. 2015; 10e0127063
        • McArthur JC
        • Stocks EA
        • Hauer P
        • Cornblath DR
        • Griffin JW
        Epidermal nerve fiber density: normative reference range and diagnostic efficiency.
        Arch Neurol. 1998; 55: 1513-1520
        • Mittal M
        • Siddiqui MR
        • Tran K
        • Reddy SP
        • Malik AB
        Reactive oxygen species in inflammation and tissue injury.
        Antioxid Redox Signal. 2014; 20: 1126-1167
        • Moore BA
        • Manthey CL
        • Johnson DL
        • Bauer AJ
        Matrix metalloproteinase-9 inhibition reduces inflammation and improves motility in murine models of postoperative ileus.
        Gastroenterology. 2011; 141: 1283-1292
        • Nishida K
        • Kuchiiwa S
        • Oiso S
        • Futagawa T
        • Masuda S
        • Takeda Y
        • Yamada K
        Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy.
        Cancer Sci. 2008; 99: 1618-1625
        • Parks WC
        • Parks WC
        • Wilson CL
        • Wilson CL
        • López-Boado YS
        • López-Boado YS
        Matrix metalloproteinases as modulators of inflammation and innate immunity.
        Nat Rev Immunol. 2004; 4: 617-629
        • Pfaffl MW
        A new mathematical model for relative quantification in real-time RT-PCR.
        Nucleic Acids Res. 2001; 29: 45e
        • Radjabi AR
        • Sawada K
        • Jagadeeswaran S
        • Eichbichler A
        • Kenny HA
        • Montag A
        • Bruno K
        • Lengyel E
        Thrombin induces tumor invasion through the induction and association of matrix metalloproteinase-9 and beta1-integrin on the cell surface.
        J Biol Chem. 2008; 283: 2822-2834
        • Rosenberg GA
        Matrix metalloproteinases and their multiple roles in neurodegenerative diseases.
        Lancet Neurol. 2009; 8: 205-216
        • Sandborn WJ
        • Bhandari BR
        • Fogel R
        • Onken J
        • Yen E
        • Zhao X
        • Jiang Z
        • Ge D
        • Xin Y
        • Ye Z
        • French D
        • Silverman JA
        • Kanwar B
        • Subramanian GM
        • McHutchison JG
        • Lee SD
        • Shackelton LM
        • Pai RK
        • Levesque BG
        • Feagan BG
        Randomised clinical trial: A phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis.
        Aliment Pharmacol Ther. 2016; 44: 157-169
        • Schappacher KA
        • Styczynski L
        • Baccei ML
        Early life vincristine exposure evokes mechanical pain hypersensitivity in the developing rat.
        Pain. 2017; 158: 1647-1655
        • Seretny M
        • Currie GL
        • Sena ES
        • Ramnarine S
        • Grant R
        • Macleod MR
        • Colvin LA
        • Fallon M
        Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.
        Pain. 2014; 155: 2461-2470
        • Sorge RE
        • Mapplebeck JCS
        • Rosen S
        • Beggs S
        • Taves S
        • Alexander JK
        • Martin LJ
        • Austin J-S
        • Sotocinal SG
        • Chen D
        • Yang M
        • Shi XQ
        • Huang H
        • Pillon NJ
        • Bilan PJ
        • Tu Y
        • Klip A
        • Ji R-R
        • Zhang J
        • Salter MW
        • Mogil JS
        Different immune cells mediate mechanical pain hypersensitivity in male and female mice.
        Nat Neurosci. 2015; 18: 1081-1083
        • Starkweather A
        • Angela
        Increased interleukin-6 activity associated with painful chemotherapy-induced peripheral neuropathy in women after breast cancer treatment.
        Nurs Res Pract Hindawi. 2010; 2010281531
        • Vandenbroucke RE
        • Libert C
        Is there new hope for therapeutic matrix metalloproteinase inhibition?.
        Nat Rev Drug Discov. 2014; 13: 904-927
        • Wang X
        • Fang H
        • Huang Z
        • Shang W
        • Hou T
        • Cheng A
        • Cheng H
        Imaging ROS signaling in cells and animals.
        J Mol Med. 2013; 91: 917-927
        • Wang X
        • Spandidos A
        • Wang H
        • Seed B
        PrimerBank: a PCR primer database for quantitative gene expression analysis, 2012 update.
        Nucleic Acids Res. 2012; 40: D1144-D1149
        • Warwick RA
        • Hanani M
        The contribution of satellite glial cells to chemotherapy-induced neuropathic pain.
        Eur J Pain. 2013; 17: 571-580
        • Weiner LM
        • Surana R
        • Wang S
        Monoclonal antibodies: Versatile platforms for cancer immunotherapy.
        Nat Rev Immunol. 2010; 10: 317-327
        • Wu Z
        • Wang S
        • Wu I
        • Mata M
        • Fink DJ
        Activation of TLR-4 to produce tumour necrosis factor-α in neuropathic pain caused by paclitaxel.
        Eur J Pain. 2015; 19: 889-898
        • Xu Z-Z
        • Kim YH
        • Bang S
        • Zhang Y
        • Berta T
        • Wang F
        • Oh SB
        • Ji R-R
        Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade.
        Nat Med. 2015; 21: 1326-1331
        • Yong VW
        Metalloproteinases: mediators of pathology and regeneration in the CNS.
        Nat Rev Neurosci. 2005; 6: 931-944
        • Yu F
        • Kamada H
        • Niizuma K
        • Endo H
        • Chan PH
        Induction of MMP-9 expression and endothelial injury by oxidative stress after spinal cord injury.
        J Neurotrauma. 2008; 25: 184-195
        • Zhang H
        • Li Y
        • De Carvalho-Barbosa M
        • Kavelaars A
        • Heijnen CJ
        • Albrecht PJ
        • Dougherty PM
        Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy-induced peripheral neuropathy.
        J Pain. 2016; 17: 775-786
        • Zhang HH
        • Yoon SY
        • Zhang HH
        • Dougherty PM
        Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of paclitaxel-induced painful neuropathy.
        J Pain. 2012; 13: 293-303
        • Zhou YQ
        • Liu Z
        • Liu ZH
        • Chen SP
        • Li M
        • Shahveranov A
        • Ye DW
        • Tian YK
        Interleukin-6: An emerging regulator of pathological pain.
        J Neuroinflammation. 2016; 13: 141