Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells.
Identifieur interne : 001064 ( Main/Exploration ); précédent : 001063; suivant : 001065Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells.
Auteurs : Aleksandar Pantovic [Serbie] ; Aleksandra Krstic ; Kristina Janjetovic ; Jelena Kocic ; Ljubica Harhaji-Trajkovic ; Diana Bugarski ; Vladimir TrajkovicSource :
- Bone [ 1873-2763 ] ; 2013.
Descripteurs français
- KwdFr :
- MESH :
- métabolisme : Adenylate kinase, Cellules souches, Sérine-thréonine kinases TOR.
- physiologie : Différenciation cellulaire.
- Autophagie, Femelle, Humains, Ostéogenèse, Transduction du signal.
English descriptors
- KwdEn :
- MESH :
- chemical , metabolism : Adenylate Kinase, TOR Serine-Threonine Kinases.
- metabolism : Stem Cells.
- physiology : Cell Differentiation.
- Autophagy, Female, Humans, Osteogenesis, Signal Transduction.
Abstract
We investigated the role of AMP-activated protein kinase (AMPK), Akt, mammalian target of rapamycin (mTOR), autophagy and their interplay in osteogenic differentiation of human dental pulp mesenchymal stem cells. The activation of various members of AMPK, Akt and mTOR signaling pathways and autophagy was analyzed by immunoblotting, while osteogenic differentiation was assessed by alkaline phosphatase staining and real-time RT-PCR/immunoblot quantification of osteocalcin, Runt-related transcription factor 2 and bone morphogenetic protein 2 mRNA and/or protein levels. Osteogenic differentiation of mesenchymal stem cells was associated with early (day 1) activation of AMPK and its target Raptor, coinciding with the inhibition of mTOR and its substrate p70S6 kinase. The early induction of autophagy was demonstrated by accumulation of autophagosome-bound LC3-II, upregulation of proautophagic beclin-1 and a decrease in the selective autophagic target p62. This was followed by the late activation of Akt/mTOR at days 3-7 of differentiation. The RNA interference-mediated silencing of AMPK, mTOR or autophagy-essential LC3β, as well as the pharmacological inhibitors of AMPK (compound C), Akt (10-DEBC hydrochloride), mTOR (rapamycin) and autophagy (bafilomycin A1, chloroquine and ammonium chloride), each suppressed mesenchymal stem cell differentiation to osteoblasts. AMPK knockdown prevented early mTOR inhibition and autophagy induction, as well as late activation of Akt/mTOR signaling, while Akt inhibition suppressed mTOR activation without affecting AMPK phosphorylation. Our data indicate that AMPK controls osteogenic differentiation of human mesenchymal stem cells through both early mTOR inhibition-mediated autophagy and late activation of Akt/mTOR signaling axis.
DOI: 10.1016/j.bone.2012.10.024
PubMed: 23111315
Affiliations:
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sortKey="Janjetovic, Kristina" sort="Janjetovic, Kristina" uniqKey="Janjetovic K" first="Kristina" last="Janjetovic">Kristina Janjetovic</name></author><author><name sortKey="Kocic, Jelena" sort="Kocic, Jelena" uniqKey="Kocic J" first="Jelena" last="Kocic">Jelena Kocic</name></author><author><name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name></author><author><name sortKey="Bugarski, Diana" sort="Bugarski, Diana" uniqKey="Bugarski D" first="Diana" last="Bugarski">Diana Bugarski</name></author><author><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2013">2013</date><idno type="RBID">pubmed:23111315</idno><idno type="pmid">23111315</idno><idno 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xml:lang="fr">Serbie</country><wicri:regionArea>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade</wicri:regionArea><wicri:noRegion>11000 Belgrade</wicri:noRegion></affiliation></author><author><name sortKey="Krstic, Aleksandra" sort="Krstic, Aleksandra" uniqKey="Krstic A" first="Aleksandra" last="Krstic">Aleksandra Krstic</name></author><author><name sortKey="Janjetovic, Kristina" sort="Janjetovic, Kristina" uniqKey="Janjetovic K" first="Kristina" last="Janjetovic">Kristina Janjetovic</name></author><author><name sortKey="Kocic, Jelena" sort="Kocic, Jelena" uniqKey="Kocic J" first="Jelena" last="Kocic">Jelena Kocic</name></author><author><name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name></author><author><name sortKey="Bugarski, Diana" sort="Bugarski, Diana" uniqKey="Bugarski D" first="Diana" last="Bugarski">Diana Bugarski</name></author><author><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name></author></analytic><series><title level="j">Bone</title><idno type="eISSN">1873-2763</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenylate Kinase (metabolism)</term><term>Autophagy (MeSH)</term><term>Cell Differentiation (physiology)</term><term>Female (MeSH)</term><term>Humans (MeSH)</term><term>Osteogenesis (MeSH)</term><term>Signal Transduction (MeSH)</term><term>Stem Cells (metabolism)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adenylate kinase (métabolisme)</term><term>Autophagie (MeSH)</term><term>Cellules souches (métabolisme)</term><term>Différenciation cellulaire (physiologie)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Ostéogenèse (MeSH)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Transduction du signal (MeSH)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adenylate Kinase</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Stem Cells</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Adenylate kinase</term><term>Cellules souches</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Différenciation cellulaire</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Cell Differentiation</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Autophagy</term><term>Female</term><term>Humans</term><term>Osteogenesis</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Autophagie</term><term>Femelle</term><term>Humains</term><term>Ostéogenèse</term><term>Transduction du signal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We investigated the role of AMP-activated protein kinase (AMPK), Akt, mammalian target of rapamycin (mTOR), autophagy and their interplay in osteogenic differentiation of human dental pulp mesenchymal stem cells. The activation of various members of AMPK, Akt and mTOR signaling pathways and autophagy was analyzed by immunoblotting, while osteogenic differentiation was assessed by alkaline phosphatase staining and real-time RT-PCR/immunoblot quantification of osteocalcin, Runt-related transcription factor 2 and bone morphogenetic protein 2 mRNA and/or protein levels. Osteogenic differentiation of mesenchymal stem cells was associated with early (day 1) activation of AMPK and its target Raptor, coinciding with the inhibition of mTOR and its substrate p70S6 kinase. The early induction of autophagy was demonstrated by accumulation of autophagosome-bound LC3-II, upregulation of proautophagic beclin-1 and a decrease in the selective autophagic target p62. This was followed by the late activation of Akt/mTOR at days 3-7 of differentiation. The RNA interference-mediated silencing of AMPK, mTOR or autophagy-essential LC3β, as well as the pharmacological inhibitors of AMPK (compound C), Akt (10-DEBC hydrochloride), mTOR (rapamycin) and autophagy (bafilomycin A1, chloroquine and ammonium chloride), each suppressed mesenchymal stem cell differentiation to osteoblasts. AMPK knockdown prevented early mTOR inhibition and autophagy induction, as well as late activation of Akt/mTOR signaling, while Akt inhibition suppressed mTOR activation without affecting AMPK phosphorylation. Our data indicate that AMPK controls osteogenic differentiation of human mesenchymal stem cells through both early mTOR inhibition-mediated autophagy and late activation of Akt/mTOR signaling axis.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">23111315</PMID><DateCompleted><Year>2013</Year><Month>03</Month><Day>25</Day></DateCompleted><DateRevised><Year>2012</Year><Month>12</Month><Day>03</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1873-2763</ISSN><JournalIssue CitedMedium="Internet"><Volume>52</Volume><Issue>1</Issue><PubDate><Year>2013</Year><Month>Jan</Month></PubDate></JournalIssue><Title>Bone</Title><ISOAbbreviation>Bone</ISOAbbreviation></Journal><ArticleTitle>Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells.</ArticleTitle><Pagination><MedlinePgn>524-31</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.bone.2012.10.024</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S8756-3282(12)01332-4</ELocationID><Abstract><AbstractText>We investigated the role of AMP-activated protein kinase (AMPK), Akt, mammalian target of rapamycin (mTOR), autophagy and their interplay in osteogenic differentiation of human dental pulp mesenchymal stem cells. The activation of various members of AMPK, Akt and mTOR signaling pathways and autophagy was analyzed by immunoblotting, while osteogenic differentiation was assessed by alkaline phosphatase staining and real-time RT-PCR/immunoblot quantification of osteocalcin, Runt-related transcription factor 2 and bone morphogenetic protein 2 mRNA and/or protein levels. Osteogenic differentiation of mesenchymal stem cells was associated with early (day 1) activation of AMPK and its target Raptor, coinciding with the inhibition of mTOR and its substrate p70S6 kinase. The early induction of autophagy was demonstrated by accumulation of autophagosome-bound LC3-II, upregulation of proautophagic beclin-1 and a decrease in the selective autophagic target p62. This was followed by the late activation of Akt/mTOR at days 3-7 of differentiation. The RNA interference-mediated silencing of AMPK, mTOR or autophagy-essential LC3β, as well as the pharmacological inhibitors of AMPK (compound C), Akt (10-DEBC hydrochloride), mTOR (rapamycin) and autophagy (bafilomycin A1, chloroquine and ammonium chloride), each suppressed mesenchymal stem cell differentiation to osteoblasts. AMPK knockdown prevented early mTOR inhibition and autophagy induction, as well as late activation of Akt/mTOR signaling, while Akt inhibition suppressed mTOR activation without affecting AMPK phosphorylation. Our data indicate that AMPK controls osteogenic differentiation of human mesenchymal stem cells through both early mTOR inhibition-mediated autophagy and late activation of Akt/mTOR signaling axis.</AbstractText><CopyrightInformation>Copyright © 2012 Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pantovic</LastName><ForeName>Aleksandar</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr Subotica 1, 11000 Belgrade, Serbia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Krstic</LastName><ForeName>Aleksandra</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Janjetovic</LastName><ForeName>Kristina</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Kocic</LastName><ForeName>Jelena</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Harhaji-Trajkovic</LastName><ForeName>Ljubica</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Bugarski</LastName><ForeName>Diana</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Trajkovic</LastName><ForeName>Vladimir</ForeName><Initials>V</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2012</Year><Month>10</Month><Day>27</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Bone</MedlineTA><NlmUniqueID>8504048</NlmUniqueID><ISSNLinking>1873-2763</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.4.3</RegistryNumber><NameOfSubstance UI="D000263">Adenylate Kinase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000263" MajorTopicYN="N">Adenylate Kinase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001343" MajorTopicYN="Y">Autophagy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002454" MajorTopicYN="N">Cell Differentiation</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010012" MajorTopicYN="Y">Osteogenesis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="Y">Signal Transduction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013234" MajorTopicYN="N">Stem Cells</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2012</Year><Month>05</Month><Day>09</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2012</Year><Month>10</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2012</Year><Month>10</Month><Day>20</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>11</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>11</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2013</Year><Month>3</Month><Day>26</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">23111315</ArticleId><ArticleId IdType="pii">S8756-3282(12)01332-4</ArticleId><ArticleId IdType="doi">10.1016/j.bone.2012.10.024</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Serbie</li></country></list><tree><noCountry><name sortKey="Bugarski, Diana" sort="Bugarski, Diana" uniqKey="Bugarski D" first="Diana" last="Bugarski">Diana Bugarski</name><name sortKey="Harhaji Trajkovic, Ljubica" sort="Harhaji Trajkovic, Ljubica" uniqKey="Harhaji Trajkovic L" first="Ljubica" last="Harhaji-Trajkovic">Ljubica Harhaji-Trajkovic</name><name sortKey="Janjetovic, Kristina" sort="Janjetovic, Kristina" uniqKey="Janjetovic K" first="Kristina" last="Janjetovic">Kristina Janjetovic</name><name sortKey="Kocic, Jelena" sort="Kocic, Jelena" uniqKey="Kocic J" first="Jelena" last="Kocic">Jelena Kocic</name><name sortKey="Krstic, Aleksandra" sort="Krstic, Aleksandra" uniqKey="Krstic A" first="Aleksandra" last="Krstic">Aleksandra Krstic</name><name sortKey="Trajkovic, Vladimir" sort="Trajkovic, Vladimir" uniqKey="Trajkovic V" first="Vladimir" last="Trajkovic">Vladimir Trajkovic</name></noCountry><country name="Serbie"><noRegion><name sortKey="Pantovic, Aleksandar" sort="Pantovic, Aleksandar" uniqKey="Pantovic A" first="Aleksandar" last="Pantovic">Aleksandar Pantovic</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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