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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2024

Open Access 01-12-2024 | Research

SPOCK2 modulates neuropathic pain by interacting with MT1-MMP to regulate astrocytic MMP-2 activation in rats with chronic constriction injury

Authors: Chenglong Wang, Yitong Xu, Miao Xu, Cong Sun, Xiaojiao Zhang, Xueshu Tao, Tao Song

Published in: Journal of Neuroinflammation | Issue 1/2024

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Abstract

Background

Neuropathic pain (NP) is a kind of intractable pain. The pathogenesis of NP remains a complicated issue for pain management practitioners. SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 2 (SPOCK2) are members of the SPOCK family that play a significant role in the development of the central nervous system. In this study, we investigated the role of SPOCK2 in the development of NP in a rat model of chronic constriction injury (CCI).

Methods

Sprague–Dawley rats were randomly grouped to establish CCI models. We examined the effects of SPOCK2 on pain hpersensitivity and spinal astrocyte activation after CCI-induced NP. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were used to reflects the pain behavioral degree. Molecular mechanisms involved in SPOCK2-mediated NP in vivo were examined by western blot analysis, immunofluorescence, immunohistochemistry, and co-immunoprecipitation. In addition, we examined the SPOCK2-mediated potential protein–protein interaction (PPI) in vitro coimmunoprecipitation (Co-IP) experiments.

Results

We founded the expression level of SPOCK2 in rat spinal cord was markedly increased after CCI-induced NP, while SPOCK2 downregulation could partially relieve pain caused by CCI. Our research showed that SPOCK2 expressed significantly increase in spinal astrocytes when CCI-induced NP. In addition, SPOCK2 could act as an upstream signaling molecule to regulate the activation of matrix metalloproteinase-2 (MMP-2), thus affecting astrocytic ERK1/2 activation and interleukin (IL)-1β production in the development of NP. Moreover, in vitro coimmunoprecipitation (Co-IP) experiments showed that SPOCK2 could interact with membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP14) to regulate MMP-2 activation by the SPARC extracellular (SPARC_EC) domain.

Conclusions

Research shows that SPOCK2 can interact with MT1-MMP to regulate MMP-2 activation, thus affecting astrocytic ERK1/2 activation and IL-1β production to achieve positive promotion of NP.
Literature
1.
Scholz J, Finnerup NB, Attal N, Aziz Q, Baron R, Bennett MI, Benoliel R, Cohen M, Cruccu G, Davis KD, et al. The IASP classification of chronic pain for ICD-11: chronic neuropathic pain. Pain. 2019;160:53–9.PubMedPubMedCentralCrossRef
2.
Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci USA. 2007;104:10655–60.ADSPubMedPubMedCentralCrossRef
3.
Ji RR, Suter MR. p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain. 2007;3:1744-8069-3–33.CrossRef
4.
Ji R-R, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE. 2004;2004:reE14–reE14.PubMedCrossRef
5.
Jin SX, Zhuang ZY, Woolf CJ, Ji RR. P38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 2003;23:4017–22.PubMedPubMedCentralCrossRef
6.
Peng J, Yi MH, Jeong H, McEwan PP, Zheng J, Wu G, Ganatra S, Ren Y, Richardson JR, Oh SB, Wu LJ. The voltage-gated proton channel Hv1 promotes microglia-astrocyte communication and neuropathic pain after peripheral nerve injury. Mol Brain. 2021;14:99.PubMedPubMedCentralCrossRef
7.
Smith PA. Neuropathic pain; what we know and what we should do about it. Front Pain Res (Lausanne). 2023;4:1220034.PubMedCrossRef
8.
Yi H, Liu S, Kashiwagi Y, Ikegami D, Huang W, Kanda H, Iida T, Liu CH, Takahashi K, Lubarsky DA, Hao S. Phosphorylated CCAAT/enhancer binding protein β contributes to rat HIV-related neuropathic pain. In vitro and in vivo studies. J Neurosci. 2018;38:555–74.PubMedPubMedCentralCrossRef
9.
Zhang LQ, Gao SJ, Sun J, Li DY, Wu JY, Song FH, Liu DQ, Zhou YQ, Mei W. DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation. J Neuroinflammation. 2022;19:129.PubMedPubMedCentralCrossRef
10.
Zhang SB, Zhao GH, Lv TR, Gong CY, Shi YQ, Nan W, Zhang HH. Bibliometric and visual analysis of microglia-related neuropathic pain from 2000 to 2021. Front Mol Neurosci. 2023;16:1142852.PubMedPubMedCentralCrossRef
11.
Yang QQ, Zhou JW. Neuroinflammation in the central nervous system: symphony of glial cells. Glia. 2019;67:1017–35.PubMedCrossRef
12.
13.
14.
15.
Gwak YS, Kang J, Unabia GC, Hulsebosch CE. Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats. Exp Neurol. 2012;234:362–72.PubMedCrossRef
16.
Hartmann U, Maurer P. Proteoglycans in the nervous system—the quest for functional roles in vivo. Matrix Biol. 2001;20:23–35.PubMedCrossRef
17.
Vannahme C, Schübel S, Herud M, Gösling S, Hülsmann H, Paulsson M, Hartmann U, Maurer P. Molecular cloning of testican-2: defining a novel calcium-binding proteoglycan family expressed in brain. J Neurochem. 1999;73:12–20.PubMedCrossRef
18.
Zhao J, Cheng M, Gai J, Zhang R, Du T, Li Q. SPOCK2 serves as a potential prognostic marker and correlates with immune infiltration in lung adenocarcinoma. Front Genet. 2020;11: 588499.PubMedPubMedCentralCrossRef
19.
Liu G, Ren F, Song Y. Upregulation of SPOCK2 inhibits the invasion and migration of prostate cancer cells by regulating the MT1-MMP/MMP2 pathway. PeerJ. 2019;7: e7163.PubMedPubMedCentralCrossRef
20.
Lou W, Ding B, Zhong G, Du C, Fan W, Fu P. Dysregulation of pseudogene/lncRNA-hsa-miR-363-3p-SPOCK2 pathway fuels stage progression of ovarian cancer. Aging (Albany NY). 2019;11:11416–39.PubMedCrossRef
21.
Hadchouel A, Durrmeyer X, Bouzigon E, Incitti R, Huusko J, Jarreau PH, Lenclen R, Demenais F, Franco-Montoya ML, Layouni I, et al. Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2011;184:1164–70.PubMedCrossRef
22.
Freidin MB, Tsepilov YA, Palmer M, Karssen LC, Suri P, Aulchenko YS, Williams FMK, Group CMW. Insight into the genetic architecture of back pain and its risk factors from a study of 509,000 individuals. Pain. 2019;160:1361–73.PubMedPubMedCentralCrossRef
23.
Bortsov AV, Parisien M, Khoury S, Martinsen AE, Lie MU, Heuch I, Hveem K, Zwart JA, Winsvold BS, Diatchenko L. Brain-specific genes contribute to chronic but not to acute back pain. Pain Rep. 2022;7: e1018.PubMedPubMedCentralCrossRef
24.
Ren F, Wang D, Wang Y, Chen P, Guo C. SPOCK2 affects the biological behavior of endometrial cancer cells by regulation of MT1-MMP and MMP2. Reprod Sci. 2020;27:1391–9.PubMedCrossRef
25.
Nakada M, Miyamori H, Yamashita J, Sato H. Testican 2 abrogates inhibition of membrane-type matrix metalloproteinases by other testican family proteins. Cancer Res. 2003;63:3364–9.PubMed
26.
Nakada M, Yamada A, Takino T, Miyamori H, Takahashi T, Yamashita J, Sato H. Suppression of membrane-type 1 matrix metalloproteinase (MMP)-mediated MMP-2 activation and tumor invasion by testican 3 and its splicing variant gene product, N-Tes. Cancer Res. 2001;61:8896–902.PubMed
27.
28.
29.
Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562–73.PubMedCrossRef
30.
Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med. 2008;14:331–6.PubMedPubMedCentralCrossRef
31.
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.PubMedPubMedCentralCrossRef
32.
Xu A, Liu M, Huang MF, Zhang Y, Hu R, Gingold JA, Liu Y, Zhu D, Chien CS, Wang WC, et al. Rewired m(6)A epitranscriptomic networks link mutant p53 to neoplastic transformation. Nat Commun. 2023;14:1694.ADSPubMedPubMedCentralCrossRef
33.
Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33:87–107.PubMedCrossRef
34.
Feng Y, Guo S, Zhao Y, Dong H, Qian J, Hu Y, Wu L, Jia Y, Zhao R. DNA 5mC and RNA m(6)A modification successively facilitates the initiation and perpetuation stages of HSC activation in liver fibrosis progression. Cell Death Differ. 2023;30:1211–20.PubMedCrossRef
35.
Wang B, Liu S, Fan B, Xu X, Chen Y, Lu R, Xu Z, Liu X. PKM2 is involved in neuropathic pain by regulating ERK and STAT3 activation in rat spinal cord. J Headache Pain. 2018;19:7.PubMedPubMedCentralCrossRef
36.
Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain. 2005;114:149–59.PubMedCrossRef
37.
Ma WY, Quirion R. Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain. 2002;99:175–84.PubMedCrossRef
38.
David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 2011;12:388–99.PubMedCrossRef
39.
Ji RR, Gereau RW, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev. 2009;60:135–48.PubMedCrossRef
40.
41.
Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci. 2006;26:3551–60.PubMedPubMedCentralCrossRef
42.
Ji R-R, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci. 1999;2:1114–9.PubMedCrossRef
43.
Karim F, Hu HJ, Adwanikar H, Kaplan D, Gereau RW. Impaired inflammatory pain and thermal hyperalgesia in mice expressing neuron-specific dominant negative mitogen activated protein kinase kinase (MEK). Mol Pain. 2006;2:1744-8069-2–2.CrossRef
44.
Karim F, Wang CC, Gereau RW. Metabotropic glutamate receptor subtypes 1 and 5 are activators of extracellular signal-regulated kinase signaling required for inflammatory pain in mice. J Neurosci. 2001;21:3771–9.PubMedPubMedCentralCrossRef
45.
Pezet S, Malcangio M, Lever IJ, Perkinton MS, Thompson SW, Williams RJ, McMahon SB. Noxious stimulation induces Trk receptor and downstream ERK phosphorylation in spinal dorsal horn. Mol Cell Neurosci. 2002;21:684–95.PubMedCrossRef
46.
Dai Y, Iwata K, Fukuoka T, Kondo E, Tokunaga A, Yamanaka H, Tachibana T, Liu Y, Noguchi K. Phosphorylation of extracellular signal-regulated kinase in primary afferent neurons by noxious stimuli and its involvement in peripheral sensitization. J Neurosci. 2002;22:7737–45.PubMedPubMedCentralCrossRef
47.
Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia. 2004;45:89–95.PubMedCrossRef
48.
Stein C, Millan MJ, Herz A. Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: alterations in behavior and nociceptive thresholds. Pharmacol Biochem Behav. 1988;31:445–51.PubMedCrossRef
49.
Gui WS, Wei X, Mai CL, Murugan M, Wu LJ, Xin WJ, Zhou LJ, Liu XG. Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents. Mol Pain. 2016;12:174480691664678.CrossRef
50.
Boakye PA, Tang SJ, Smith PA. Mediators of neuropathic pain; focus on spinal microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt ligands, and interleukin 1β. Front Pain Res (Lausanne). 2021;2: 698157.PubMedCrossRef
51.
Yamashita T, Kamikaseda S, Tanaka A, Tozaki-Saitoh H, Caaveiro JMM, Inoue K, Tsuda M. New inhibitory effects of cilnidipine on microglial P2X7 receptors and IL-1β release: an involvement in its alleviating effect on neuropathic pain. Cells. 2021;10:434.PubMedPubMedCentralCrossRef
52.
Tang J, Zhu C, Li ZH, Liu XY, Sun SK, Zhang T, Luo ZJ, Zhang H, Li WY. Inhibition of the spinal astrocytic JNK/MCP-1 pathway activation correlates with the analgesic effects of tanshinone IIA sulfonate in neuropathic pain. J Neuroinflammation. 2015;12:57.PubMedPubMedCentralCrossRef
53.
Guo CH, Bai L, Wu HH, Yang J, Cai GH, Wang X, Wu SX, Ma W. The analgesic effect of rolipram is associated with the inhibition of the activation of the spinal astrocytic JNK/CCL2 pathway in bone cancer pain. Int J Mol Med. 2016;38:1433–42.PubMedPubMedCentralCrossRef
54.
Pan C, Wang C, Zhang L, Song L, Chen Y, Liu B, Liu WT, Hu L, Pan Y. Procyanidins attenuate neuropathic pain by suppressing matrix metalloproteinase-9/2. J Neuroinflammation. 2018;15:187.PubMedPubMedCentralCrossRef
55.
Hong S, Remacle AG, Shiryaev SA, Choi W, Hullugundi SK, Dolkas J, Angert M, Nishihara T, Yaksh TL, Strongin AY, Shubayev VI. Reciprocal relationship between membrane type 1 matrix metalloproteinase and the algesic peptides of myelin basic protein contributes to chronic neuropathic pain. Brain Behav Immun. 2017;60:282–92.PubMedCrossRef
56.
McClung HM, Thomas SL, Osenkowski P, Toth M, Menon P, Raz A, Fridman R, Rempel SA. SPARC upregulates MT1-MMP expression, MMP-2 activation, and the secretion and cleavage of galectin-3 in U87MG glioma cells. Neurosci Lett. 2007;419:172–7.PubMedPubMedCentralCrossRef
57.
Matsuzaki T, Keene DR, Nishimoto E, Noda M. Reversion-inducing cysteine-rich protein with Kazal motifs and MT1-MMP promote the formation of robust fibrillin fibers. J Cell Physiol. 2021;236:1980–95.PubMedCrossRef
58.
59.
Ray PR, Shiers S, Caruso JP, Tavares-Ferreira D, Sankaranarayanan I, Uhelski ML, Li Y, North RY, Tatsui C, Dussor G, et al. RNA profiling of human dorsal root ganglia reveals sex differences in mechanisms promoting neuropathic pain. Brain. 2023;146:749–66.PubMedCrossRef
Metadata
Title
SPOCK2 modulates neuropathic pain by interacting with MT1-MMP to regulate astrocytic MMP-2 activation in rats with chronic constriction injury
Authors
Chenglong Wang
Yitong Xu
Miao Xu
Cong Sun
Xiaojiao Zhang
Xueshu Tao
Tao Song
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-024-03051-5

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