NR4A1 promotes TNF-α-induced chondrocyte death and migration injury via activating the AMPK/Drp1/mitochondrial fission pathway
Identifieur interne : 000600 ( Pmc/Curation ); précédent : 000599; suivant : 000601NR4A1 promotes TNF-α-induced chondrocyte death and migration injury via activating the AMPK/Drp1/mitochondrial fission pathway
Auteurs : Zhibo Zheng ; Shuai Xiang [République populaire de Chine] ; Yingjie Wang ; Yulei Dong ; Zeng Li ; Yongbo Xiang ; Yanyan Bian ; Bin Feng ; Bo Yang ; Xisheng WengSource :
- International Journal of Molecular Medicine [ 1107-3756 ] ; 2019.
Abstract
Nuclear receptor subfamily 4 group A member 1 (NR4A1)-induced chondrocyte death plays a critical role in the development of osteoarthritis through poorly defined mechanisms. The present study aimed to investigate the role of NR4A1 in regulating chondrocyte death in response to tumor necrosis factor-α (TNF-α) and cycloheximide (CHX) treatment, with a focus on mitochondrial fission and the AMP-activated protein kinase (AMPK) signaling pathway. The results demonstrated that NR4A1 was significantly upregulated in TNF-α and CHX exposed chondrocytes. Increased NR4A1 triggered mitochondrial fission via the AMPK/dynamin-related protein 1 (Drp1) pathway, resulting in mitochondrial dysfunction, and mitochondrial permeability transition pore (mPTP) opening-related cell death. Furthermore, excessive mitochondrial fission impaired chondrocyte migration through imbalance of F-actin homeo-stasis. Inhibiting NR4A1 attenuated TNF-α and CHX-induced mitochondrial fission and, thus, reduced mitochondrial dysfunction in chondrocytes, mPTP opening-related cell death and migration injury. Altogether, the present data confirmed that mitochondrial fission was involved in NR4A1-mediated chondrocyte injury via regulation of mitochondrial dysfunction, mPTP opening-induced cell death and F-actin-related migratory inhibition.
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DOI: 10.3892/ijmm.2019.4398
PubMed: 31746366
PubMed Central: 6889925
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Zhibo Zheng<affiliation><nlm:aff id="af2-ijmm-45-01-0151">Department of International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730</nlm:aff><wicri:noCountry code="subfield">Beijing 100730</wicri:noCountry></affiliation>Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">NR4A1 promotes TNF-α-induced chondrocyte death and migration injury via activating the AMPK/Drp1/mitochondrial fission pathway</title><author><name sortKey="Zheng, Zhibo" sort="Zheng, Zhibo" uniqKey="Zheng Z" first="Zhibo" last="Zheng">Zhibo Zheng</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation><affiliation><nlm:aff id="af2-ijmm-45-01-0151">Department of International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730</nlm:aff><wicri:noCountry code="subfield">Beijing 100730</wicri:noCountry></affiliation></author><author><name sortKey="Xiang, Shuai" sort="Xiang, Shuai" uniqKey="Xiang S" first="Shuai" last="Xiang">Shuai Xiang</name><affiliation wicri:level="1"><nlm:aff id="af3-ijmm-45-01-0151">Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Yingjie" sort="Wang, Yingjie" uniqKey="Wang Y" first="Yingjie" last="Wang">Yingjie Wang</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Dong, Yulei" sort="Dong, Yulei" uniqKey="Dong Y" first="Yulei" last="Dong">Yulei Dong</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Li, Zeng" sort="Li, Zeng" uniqKey="Li Z" first="Zeng" last="Li">Zeng Li</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Xiang, Yongbo" sort="Xiang, Yongbo" uniqKey="Xiang Y" first="Yongbo" last="Xiang">Yongbo Xiang</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Bian, Yanyan" sort="Bian, Yanyan" uniqKey="Bian Y" first="Yanyan" last="Bian">Yanyan Bian</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Feng, Bin" sort="Feng, Bin" uniqKey="Feng B" first="Bin" last="Feng">Bin Feng</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Yang, Bo" sort="Yang, Bo" uniqKey="Yang B" first="Bo" last="Yang">Bo Yang</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Weng, Xisheng" sort="Weng, Xisheng" uniqKey="Weng X" first="Xisheng" last="Weng">Xisheng Weng</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31746366</idno><idno type="pmc">6889925</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889925</idno><idno type="RBID">PMC:6889925</idno><idno type="doi">10.3892/ijmm.2019.4398</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000600</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000600</idno><idno type="wicri:Area/Pmc/Curation">000600</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000600</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">NR4A1 promotes TNF-α-induced chondrocyte death and migration injury via activating the AMPK/Drp1/mitochondrial fission pathway</title><author><name sortKey="Zheng, Zhibo" sort="Zheng, Zhibo" uniqKey="Zheng Z" first="Zhibo" last="Zheng">Zhibo Zheng</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation><affiliation><nlm:aff id="af2-ijmm-45-01-0151">Department of International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730</nlm:aff><wicri:noCountry code="subfield">Beijing 100730</wicri:noCountry></affiliation></author><author><name sortKey="Xiang, Shuai" sort="Xiang, Shuai" uniqKey="Xiang S" first="Shuai" last="Xiang">Shuai Xiang</name><affiliation wicri:level="1"><nlm:aff id="af3-ijmm-45-01-0151">Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Yingjie" sort="Wang, Yingjie" uniqKey="Wang Y" first="Yingjie" last="Wang">Yingjie Wang</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Dong, Yulei" sort="Dong, Yulei" uniqKey="Dong Y" first="Yulei" last="Dong">Yulei Dong</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Li, Zeng" sort="Li, Zeng" uniqKey="Li Z" first="Zeng" last="Li">Zeng Li</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Xiang, Yongbo" sort="Xiang, Yongbo" uniqKey="Xiang Y" first="Yongbo" last="Xiang">Yongbo Xiang</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Bian, Yanyan" sort="Bian, Yanyan" uniqKey="Bian Y" first="Yanyan" last="Bian">Yanyan Bian</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Feng, Bin" sort="Feng, Bin" uniqKey="Feng B" first="Bin" last="Feng">Bin Feng</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Yang, Bo" sort="Yang, Bo" uniqKey="Yang B" first="Bo" last="Yang">Bo Yang</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author><author><name sortKey="Weng, Xisheng" sort="Weng, Xisheng" uniqKey="Weng X" first="Xisheng" last="Weng">Xisheng Weng</name><affiliation><nlm:aff id="af1-ijmm-45-01-0151">Department of Orthopedic Surgery</nlm:aff></affiliation></author></analytic><series><title level="j">International Journal of Molecular Medicine</title><idno type="ISSN">1107-3756</idno><idno type="eISSN">1791-244X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Nuclear receptor subfamily 4 group A member 1 (NR4A1)-induced chondrocyte death plays a critical role in the development of osteoarthritis through poorly defined mechanisms. The present study aimed to investigate the role of NR4A1 in regulating chondrocyte death in response to tumor necrosis factor-α (TNF-α) and cycloheximide (CHX) treatment, with a focus on mitochondrial fission and the AMP-activated protein kinase (AMPK) signaling pathway. The results demonstrated that NR4A1 was significantly upregulated in TNF-α and CHX exposed chondrocytes. Increased NR4A1 triggered mitochondrial fission via the AMPK/dynamin-related protein 1 (Drp1) pathway, resulting in mitochondrial dysfunction, and mitochondrial permeability transition pore (mPTP) opening-related cell death. Furthermore, excessive mitochondrial fission impaired chondrocyte migration through imbalance of F-actin homeo-stasis. Inhibiting NR4A1 attenuated TNF-α and CHX-induced mitochondrial fission and, thus, reduced mitochondrial dysfunction in chondrocytes, mPTP opening-related cell death and migration injury. Altogether, the present data confirmed that mitochondrial fission was involved in NR4A1-mediated chondrocyte injury via regulation of mitochondrial dysfunction, mPTP opening-induced cell death and F-actin-related migratory inhibition.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author><author><name sortKey="Lin, L" uniqKey="Lin L">L Lin</name></author><author><name sortKey="Zou, R" uniqKey="Zou R">R Zou</name></author><author><name sortKey="Wen, C" uniqKey="Wen C">C Wen</name></author><author><name sortKey="Wang, Z" uniqKey="Wang Z">Z Wang</name></author><author><name sortKey="Lin, F" uniqKey="Lin F">F Lin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Song E, K" uniqKey="Song E K">K Song E</name></author><author><name sortKey="Jeon, J" uniqKey="Jeon J">J Jeon</name></author><author><name sortKey="Jang, Dg" uniqKey="Jang D">DG 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Med</journal-id><journal-id journal-id-type="iso-abbrev">Int. J. Mol. Med</journal-id><journal-id journal-id-type="publisher-id">IJMM</journal-id><journal-title-group><journal-title>International Journal of Molecular Medicine</journal-title></journal-title-group><issn pub-type="ppub">1107-3756</issn><issn pub-type="epub">1791-244X</issn><publisher><publisher-name>D.A. Spandidos</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31746366</article-id><article-id pub-id-type="pmc">6889925</article-id><article-id pub-id-type="doi">10.3892/ijmm.2019.4398</article-id><article-id pub-id-type="publisher-id">ijmm-45-01-0151</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>NR4A1 promotes TNF-α-induced chondrocyte death and migration injury via activating the AMPK/Drp1/mitochondrial fission pathway</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zheng</surname><given-names>Zhibo</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref><xref ref-type="aff" rid="af2-ijmm-45-01-0151">2</xref><xref rid="fn1-ijmm-45-01-0151" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Xiang</surname><given-names>Shuai</given-names></name><xref ref-type="aff" rid="af3-ijmm-45-01-0151">3</xref><xref rid="fn1-ijmm-45-01-0151" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Yingjie</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref></contrib><contrib contrib-type="author"><name><surname>Dong</surname><given-names>Yulei</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Zeng</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref></contrib><contrib contrib-type="author"><name><surname>Xiang</surname><given-names>Yongbo</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref></contrib><contrib contrib-type="author"><name><surname>Bian</surname><given-names>Yanyan</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Bin</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Bo</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref></contrib><contrib contrib-type="author"><name><surname>Weng</surname><given-names>Xisheng</given-names></name><xref ref-type="aff" rid="af1-ijmm-45-01-0151">1</xref><xref ref-type="corresp" rid="c1-ijmm-45-01-0151"></xref></contrib></contrib-group><aff id="af1-ijmm-45-01-0151"><label>1</label>Department of Orthopedic Surgery</aff><aff id="af2-ijmm-45-01-0151"><label>2</label>Department of International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730</aff><aff id="af3-ijmm-45-01-0151"><label>3</label>Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China</aff><author-notes><corresp id="c1-ijmm-45-01-0151">Correspondence to: Professor Xisheng Weng, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Shuaifuyuan Wangfujing, Dongcheng, Beijing 100730, P.R. China, E-mail: <email>xshweng@medmedmail.com.cn</email></corresp><fn id="fn1-ijmm-45-01-0151" fn-type="equal"><label>*</label><p>Contributed equally</p></fn></author-notes><pub-date pub-type="ppub"><month>1</month><year>2020</year></pub-date><pub-date pub-type="epub"><day>08</day><month>11</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>08</day><month>11</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>45</volume><issue>1</issue><fpage>151</fpage><lpage>161</lpage><history><date date-type="received"><day>28</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>27</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>Copyright: © Zheng et al.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc-nd/4.0/">Creative Commons Attribution-NonCommercial-NoDerivs License</ext-link>, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</license-p></license></permissions><abstract><p>Nuclear receptor subfamily 4 group A member 1 (NR4A1)-induced chondrocyte death plays a critical role in the development of osteoarthritis through poorly defined mechanisms. The present study aimed to investigate the role of NR4A1 in regulating chondrocyte death in response to tumor necrosis factor-α (TNF-α) and cycloheximide (CHX) treatment, with a focus on mitochondrial fission and the AMP-activated protein kinase (AMPK) signaling pathway. The results demonstrated that NR4A1 was significantly upregulated in TNF-α and CHX exposed chondrocytes. Increased NR4A1 triggered mitochondrial fission via the AMPK/dynamin-related protein 1 (Drp1) pathway, resulting in mitochondrial dysfunction, and mitochondrial permeability transition pore (mPTP) opening-related cell death. Furthermore, excessive mitochondrial fission impaired chondrocyte migration through imbalance of F-actin homeo-stasis. Inhibiting NR4A1 attenuated TNF-α and CHX-induced mitochondrial fission and, thus, reduced mitochondrial dysfunction in chondrocytes, mPTP opening-related cell death and migration injury. Altogether, the present data confirmed that mitochondrial fission was involved in NR4A1-mediated chondrocyte injury via regulation of mitochondrial dysfunction, mPTP opening-induced cell death and F-actin-related migratory inhibition.</p></abstract><kwd-group><kwd>osteoarthritis</kwd><kwd>nuclear receptor subfamily 4 group A member 1</kwd><kwd>AMP-activated protein kinase</kwd><kwd>mitochondrial fission</kwd></kwd-group></article-meta></front><floats-group><fig id="f1-ijmm-45-01-0151" orientation="portrait" position="float"><label>Figure 1</label><caption><p>NR4A1 upregulation is associated with chondrocyte death in osteoarthritis. (A) Cell viability was measured by MTT assay. Treatment with TNF-α and CHX for 24 h reduced chondrocyte viability in a time-dependent manner. (B) The expression of NR4A1 was measured by western blotting. (C) NR4A1 expression was significantly increased by TNF-α and CHX treatment. (D) Transfection efficiency was confirmed by western blotting. (e) The images of western blotting. (F) Knockdown of NR4A1 had no effect on chondrocyte viability. The role of NR4A1 on chondrocyte survival was measured by (G) lDH release assay, (H) MTT assay and (I) Annexin V/PI flow cytometric analysis. (J) The images of Annexin V/PI flow cytometric analysis. <sup>*</sup>P<0.05 vs. ctrl group. #P<0.05 vs. TNF-α and CHX group. ctrl, control; TNF-α, tumor necrosis factor-α; NR4A1, nuclear receptor subfamily 4 group A member 1; lDH, lactate dehydrogenase; PI, propidium iodide; si, small interfering RNA; CHX, cycloheximide.</p></caption><graphic xlink:href="IJMM-45-01-0151-g00"></graphic></fig><fig id="f2-ijmm-45-01-0151" orientation="portrait" position="float"><label>Figure 2</label><caption><p>NR4A1 upregulation is associated with chondrocyte death in osteoarthritis. (A) Inhibiting NR4A1 repressed mPTP opening in chondrocytes under TNF-α and CHX treatment. (B) Mitochondrial membrane potential was assessed by JC-1 assay. (C) The images of mitochondrial membrane potential (scale bars, 100 <italic>µ</italic>m). (D) Cell viability was measured by MTT assay. Repressing mPTP opening contributed to chondrocyte survival, which was similar to NR4A1-knockdown. (E) The change of mitochondrial length. (F) Mitochondria of chondrocytes are labeled with anti-TOM20 antibody to determine the number of cells with mitochondria fragmentation (scale bars, 10 <italic>µ</italic>m). (G) The mPTP opening time. (H) lDH release. (I) The viability of chondrocytes was measured by calcein AM/ethD-1 flow cytometric analysis. (J) Inhibiting mitochondrial fission reduced chondrocyte death. <sup>*</sup>P<0.05 vs. ctrl group. <sup>#</sup>P<0.05 vs. TNF-α and CHX group. ctrl, control; TNF-α, tumor necrosis factor-α; NR4A1, nuclear receptor subfamily 4 group A member 1; lDH, lactate dehydrogenase; si, small interfering RNA; mPTP, mitochondrial permeability transition pore; CsA, cyclosporine A; ethD-1, ethidium homodimer-1; CHX, cycloheximide.</p></caption><graphic xlink:href="IJMM-45-01-0151-g01"></graphic></fig><fig id="f3-ijmm-45-01-0151" orientation="portrait" position="float"><label>Figure 3</label><caption><p>NR4A1 contributes to mitochondrial dysfunction via excessive mitochondrial fission. (A) The percentage of double-stranded mtDNA indicates mtDNA strand breaks. (B) mtDNA copy number was assessed by complex IV segment. (C) The transcript level of mtDNA was measured by ND1, the light chain of mtDNA, and COXI, and the heavy chain of mtDNA. (D) Change in ATP contents. (e) The expression of mitochondrial eTCx was measured by western blot analysis. (F) TNF-α and CHX inhibited the content of ETCx. (G) Changes in ETCx I, II and V activities. (H) The effect of NR4A1 on state 3 respiration in chondrocytes under TNF-α and CHX stimulation. (I) The effect of NR4A1 on state 4 respiration in chondrocytes under TNF-α and CHX stimulation. (J) Change of mitoROS (scale bar, 10 <italic>µ</italic>m). <sup>*</sup>P<0.05 vs. ctrl group. <sup>#</sup>P<0.05 vs. TNF-α and CHX group. ctrl, control; TNF-α, tumor necrosis factor-α; NR4A1, nuclear receptor subfamily 4 group A member 1; si, small interfering RNA; TNF-α, tumor necrosis factor-α; mtDNA, mitochondrial DNA; mitoROS, mitochondrial reactive oxygen species; CII-core2, complex III subunit core; CII-30, complex II; CIV-II, complex IV subunit II; CI-20, complex I subunit NDUFB8; ND-1, NADH dehydrogenase subunit 1; COX1, cytochrome c oxidase subunit I; eTCx, electron transport chain complexes; CHX, cycloheximide.</p></caption><graphic xlink:href="IJMM-45-01-0151-g02"></graphic></fig><fig id="f4-ijmm-45-01-0151" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Mitochondrial fission reduces chondrocyte migration via F-actin homeostasis. (A) Cellular migration was measured by Transwell assays (scale bar, 100 <italic>µ</italic>m). (B) Fluorescence staining was also used to observe changes in F-actin (scale bar, 10 <italic>µ</italic>m). (C) Western blot assays were used to detect changes in the expression of (D) F-actin and (E) G-actin. <sup>*</sup>P<0.05 vs. ctrl group. <sup>#</sup>P<0.05 vs. TNF-α and CHX group. ctrl, control; TNF-α, tumor necrosis factor-α; si, small interfering RNA; Jasp, jasplakinolide; CHX, cycloheximide.</p></caption><graphic xlink:href="IJMM-45-01-0151-g03"></graphic></fig><fig id="f5-ijmm-45-01-0151" orientation="portrait" position="float"><label>Figure 5</label><caption><p>NR4A1 regulates mitochondrial fission via the AMPK/Drp1 pathway. AI, an activator of the AMPK pathway, was used as the positive control and cC, an inhibitor of the AMPK pathway, was used as the negative control. (A) Western blot analysis were used to measure the expression of (B) p-AMPK, (C) cyto-Drp1, (D) mito-Drp1 and (e) p-Drp1. (F) NR4A1 represses AMPK activation as indicated by an increased AMP/ATP ratio following transfection with siNR4A1. <sup>*</sup>P<0.05 vs. ctrl group. <sup>#</sup>P<0.05 vs. TNF-α and CHX group. <sup>&</sup>P<0.05 vs. TNF-α and CHX+siNR4A1 group. AI, AICAR; cC, compound C; ctrl, control; TNF-α, tumor necrosis factor-α; si, small interfering RNA; p, phoshphorylated; t, total; cyto, cytoplasmic; mito, mitochondrial; AMPK, AMP-activated protein kinase; Drp1, dynamin-related protein 1; NR4A1, nuclear receptor subfamily 4 group A member 1; CHX, cycloheximide.</p></caption><graphic xlink:href="IJMM-45-01-0151-g04"></graphic></fig><fig id="f6-ijmm-45-01-0151" orientation="portrait" position="float"><label>Figure 6</label><caption><p>TNF-α and CHX treatment elevates chondrocyte death and inhibits chondrocyte migration <italic>in vitro</italic> by initiating fatal mitochondrial fission and interrupting the NA4A1-AMPK signaling pathway. TNF-α, tumor necrosis factor-α; NR4A1, nuclear receptor subfamily 4 group A member 1; AMPK, AMP-activated protein kinase; mPTP, mitochondrial permeability transition pore; CHX, cycloheximide.</p></caption><graphic xlink:href="IJMM-45-01-0151-g05"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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