A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients
Identifieur interne : 000029 ( Pmc/Curation ); précédent : 000028; suivant : 000030A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients
Auteurs : Jian-Da Ma [République populaire de Chine] ; Jun Jing [République populaire de Chine] ; Jun-Wei Wang [République populaire de Chine] ; Tao Yan [République populaire de Chine] ; Qian-Hua Li [République populaire de Chine] ; Ying-Qian Mo [République populaire de Chine] ; Dong-Hui Zheng [République populaire de Chine] ; Jin-Long Gao [Australie] ; Ky-Anh Nguyen [Australie] ; Lie Dai [République populaire de Chine]Source :
- Arthritis Research & Therapy [ 1478-6354 ] ; 2019.
Abstract
Anti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats—suggesting it may be a potent drug for rheumatoid arthritis (RA) therapy. We aimed to investigate its effect on the invasive property of fibroblast-like synoviocytes (FLS) from patients with RA.
Synovial tissues were obtained by closed needle biopsy from active RA patients, and FLS were isolated and cultured in vitro. RA-FLS were treated with artesunate at various concentrations, while methotrexate or hydroxychloroquine was employed as comparator drugs. Cell viability, proliferation, cell cycle, apoptosis, migration, invasion, and pseudopodium formation of RA-FLS were assessed by CCK-8 assays, EdU staining, Annexin V-FITC/PI staining, transwell assays, or F-actin staining, respectively. Further, relative changes of expressed proteases were analyzed by Proteome profiler human protease array and verified by quantitative real-time PCR (qPCR), Western blot, and ELISA. The expression of signaling molecules of MAPK, NF-κB, AP-1, and PI3K/Akt pathways were measured by qPCR and Western blot. PDK-1 knockdown by specific inhibitor AR-12 or siRNA transfection was used to verify the pharmacological mechanism of artesunate on RA-FLS.
Artesunate significantly inhibited the migration and invasion of RA-FLS in a dose-dependent manner with or without TNF-α stimulation. The effect was mediated through artesunate inhibition of MMP-2 and MMP-9 production, and pre-treatment with exogenous MMP-9 reversed the inhibitory effect of artesunate on RA-FLS invasion. Artesunate had a stronger inhibitory effect on migration and invasion of RA-FLS as well as greater anti-inflammatory effect than those of hydroxychloroquine. Similar inhibitory effect was detected between artesunate and methotrexate, and synergy was observed when combined. Mechanistically, artesunate significantly inhibited PDK-1 expression as well as Akt and RSK2 phosphorylation—in a similar manner to PDK-1-specific inhibitor AR-12 or PDK-1 knockdown by siRNA transfection. This inhibition results in suppression of RA-FLS migration and invasion as well as decreased MMP-2 and MMP-9 expression.
Our study demonstrates artesunate is capable of inhibiting migration and invasion of RA-FLS through suppression of PDK1-induced activation of Akt and RSK2 phosphorylation—suggesting that artesunate may be a potential disease-modifying anti-rheumatic drug for RA.
The online version of this article (10.1186/s13075-019-1935-6) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s13075-019-1935-6
PubMed: 31234900
PubMed Central: 6591920
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<front><div type="abstract" xml:lang="en"><sec><title>Introduction</title>
<p id="Par1">Anti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats—suggesting it may be a potent drug for rheumatoid arthritis (RA) therapy. We aimed to investigate its effect on the invasive property of fibroblast-like synoviocytes (FLS) from patients with RA.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">Synovial tissues were obtained by closed needle biopsy from active RA patients, and FLS were isolated and cultured in vitro. RA-FLS were treated with artesunate at various concentrations, while methotrexate or hydroxychloroquine was employed as comparator drugs. Cell viability, proliferation, cell cycle, apoptosis, migration, invasion, and pseudopodium formation of RA-FLS were assessed by CCK-8 assays, EdU staining, Annexin V-FITC/PI staining, transwell assays, or F-actin staining, respectively. Further, relative changes of expressed proteases were analyzed by Proteome profiler human protease array and verified by quantitative real-time PCR (qPCR), Western blot, and ELISA. The expression of signaling molecules of MAPK, NF-κB, AP-1, and PI3K/Akt pathways were measured by qPCR and Western blot. PDK-1 knockdown by specific inhibitor AR-12 or siRNA transfection was used to verify the pharmacological mechanism of artesunate on RA-FLS.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">Artesunate significantly inhibited the migration and invasion of RA-FLS in a dose-dependent manner with or without TNF-α stimulation. The effect was mediated through artesunate inhibition of MMP-2 and MMP-9 production, and pre-treatment with exogenous MMP-9 reversed the inhibitory effect of artesunate on RA-FLS invasion. Artesunate had a stronger inhibitory effect on migration and invasion of RA-FLS as well as greater anti-inflammatory effect than those of hydroxychloroquine. Similar inhibitory effect was detected between artesunate and methotrexate, and synergy was observed when combined. Mechanistically, artesunate significantly inhibited PDK-1 expression as well as Akt and RSK2 phosphorylation—in a similar manner to PDK-1-specific inhibitor AR-12 or PDK-1 knockdown by siRNA transfection. This inhibition results in suppression of RA-FLS migration and invasion as well as decreased MMP-2 and MMP-9 expression.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">Our study demonstrates artesunate is capable of inhibiting migration and invasion of RA-FLS through suppression of PDK1-induced activation of Akt and RSK2 phosphorylation—suggesting that artesunate may be a potential disease-modifying anti-rheumatic drug for RA.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s13075-019-1935-6) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Arthritis Res Ther</journal-id>
<journal-id journal-id-type="iso-abbrev">Arthritis Res. Ther</journal-id>
<journal-title-group><journal-title>Arthritis Research & Therapy</journal-title>
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<issn pub-type="ppub">1478-6354</issn>
<issn pub-type="epub">1478-6362</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
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<article-meta><article-id pub-id-type="pmid">31234900</article-id>
<article-id pub-id-type="pmc">6591920</article-id>
<article-id pub-id-type="publisher-id">1935</article-id>
<article-id pub-id-type="doi">10.1186/s13075-019-1935-6</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
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<title-group><article-title>A novel function of artesunate on inhibiting migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients</article-title>
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<address><email>majd@mail.sysu.edu.cn</email>
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<address><email>jingj3@mail2.sysu.edu.cn</email>
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<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2360 039X</institution-id>
<institution-id institution-id-type="GRID">grid.12981.33</institution-id>
<institution>Department of Rheumatology, Sun Yat-Sen Memorial Hospital,</institution>
<institution>Sun Yat-Sen University,</institution>
</institution-wrap>
Guangzhou, 510120 People’s Republic of China</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2360 039X</institution-id>
<institution-id institution-id-type="GRID">grid.12981.33</institution-id>
<institution>Zhongshan School of Medicine,</institution>
<institution>Sun Yat-Sen University,</institution>
</institution-wrap>
Guangzhou, People’s Republic of China</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 834X</institution-id>
<institution-id institution-id-type="GRID">grid.1013.3</institution-id>
<institution>Institute of Dental Research, Sydney Dental School,</institution>
<institution>The University of Sydney,</institution>
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Sydney, NSW Australia</aff>
</contrib-group>
<pub-date pub-type="epub"><day>24</day>
<month>6</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>24</day>
<month>6</month>
<year>2019</year>
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<pub-date pub-type="ppub"><year>2019</year>
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<volume>21</volume>
<elocation-id>153</elocation-id>
<history><date date-type="received"><day>2</day>
<month>1</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>6</day>
<month>6</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s). 2019</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><sec><title>Introduction</title>
<p id="Par1">Anti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats—suggesting it may be a potent drug for rheumatoid arthritis (RA) therapy. We aimed to investigate its effect on the invasive property of fibroblast-like synoviocytes (FLS) from patients with RA.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">Synovial tissues were obtained by closed needle biopsy from active RA patients, and FLS were isolated and cultured in vitro. RA-FLS were treated with artesunate at various concentrations, while methotrexate or hydroxychloroquine was employed as comparator drugs. Cell viability, proliferation, cell cycle, apoptosis, migration, invasion, and pseudopodium formation of RA-FLS were assessed by CCK-8 assays, EdU staining, Annexin V-FITC/PI staining, transwell assays, or F-actin staining, respectively. Further, relative changes of expressed proteases were analyzed by Proteome profiler human protease array and verified by quantitative real-time PCR (qPCR), Western blot, and ELISA. The expression of signaling molecules of MAPK, NF-κB, AP-1, and PI3K/Akt pathways were measured by qPCR and Western blot. PDK-1 knockdown by specific inhibitor AR-12 or siRNA transfection was used to verify the pharmacological mechanism of artesunate on RA-FLS.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">Artesunate significantly inhibited the migration and invasion of RA-FLS in a dose-dependent manner with or without TNF-α stimulation. The effect was mediated through artesunate inhibition of MMP-2 and MMP-9 production, and pre-treatment with exogenous MMP-9 reversed the inhibitory effect of artesunate on RA-FLS invasion. Artesunate had a stronger inhibitory effect on migration and invasion of RA-FLS as well as greater anti-inflammatory effect than those of hydroxychloroquine. Similar inhibitory effect was detected between artesunate and methotrexate, and synergy was observed when combined. Mechanistically, artesunate significantly inhibited PDK-1 expression as well as Akt and RSK2 phosphorylation—in a similar manner to PDK-1-specific inhibitor AR-12 or PDK-1 knockdown by siRNA transfection. This inhibition results in suppression of RA-FLS migration and invasion as well as decreased MMP-2 and MMP-9 expression.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">Our study demonstrates artesunate is capable of inhibiting migration and invasion of RA-FLS through suppression of PDK1-induced activation of Akt and RSK2 phosphorylation—suggesting that artesunate may be a potential disease-modifying anti-rheumatic drug for RA.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s13075-019-1935-6) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Artesunate</kwd>
<kwd>Rheumatoid arthritis</kwd>
<kwd>Fibroblast-like synoviocytes</kwd>
<kwd>Migration</kwd>
<kwd>Invasion</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100001809</institution-id>
<institution>National Natural Science Foundation of China</institution>
</institution-wrap>
</funding-source>
<award-id>81671612</award-id>
<award-id>81801606</award-id>
<principal-award-recipient><name><surname>Ma</surname>
<given-names>Jian-Da</given-names>
</name>
<name><surname>Dai</surname>
<given-names>Lie</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100003453</institution-id>
<institution>Natural Science Foundation of Guangdong Province</institution>
</institution-wrap>
</funding-source>
<award-id>2017A030313576</award-id>
<award-id>2017A030310236 and 2018A030313541</award-id>
<principal-award-recipient><name><surname>Ma</surname>
<given-names>Jian-Da</given-names>
</name>
<name><surname>Dai</surname>
<given-names>Lie</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>Guangdong Medical Research Foundation (CN)</institution>
</funding-source>
<award-id>A2017109</award-id>
<principal-award-recipient><name><surname>Ma</surname>
<given-names>Jian-Da</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>Fundamental Research Funds for the Central Universities</institution>
</funding-source>
<award-id>17ykjc12</award-id>
<principal-award-recipient><name><surname>Dai</surname>
<given-names>Lie</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>Scientific Program of Traditional Chinese Medicine Bureau of Guangdong Province </institution>
</funding-source>
<award-id>20161058</award-id>
<principal-award-recipient><name><surname>Dai</surname>
<given-names>Lie</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>Scientific Program of Traditional Chinese Medicine Bureau of Guangdong Province</institution>
</funding-source>
<award-id>20181058</award-id>
<principal-award-recipient><name><surname>Zheng</surname>
<given-names>Dong-Hui</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
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