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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells <italic>in vitro</italic> and bone formation <italic>in vivo</italic></title><author><name sortKey="Xu, Song" sort="Xu, Song" uniqKey="Xu S" first="Song" last="Xu">Song Xu</name><affiliation><nlm:aff id="aff1"><institution>Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital</institution>, Tianjin 300052,<country>China</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="De Veirman, Kim" sort="De Veirman, Kim" uniqKey="De Veirman K" first="Kim" last="De Veirman">Kim De Veirman</name><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Evans, Holly" sort="Evans, Holly" uniqKey="Evans H" first="Holly" last="Evans">Holly Evans</name><affiliation><nlm:aff id="aff4"><institution>Department of Human Metabolism, University of Sheffield Medical School</institution>, Sheffield,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Santini, Gaia Cecilia" sort="Santini, Gaia Cecilia" uniqKey="Santini G" first="Gaia Cecilia" last="Santini">Gaia Cecilia Santini</name><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Vande Broek, Isabelle" sort="Vande Broek, Isabelle" uniqKey="Vande Broek I" first="Isabelle" last="Vande Broek">Isabelle Vande Broek</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Leleu, Xavier" sort="Leleu, Xavier" uniqKey="Leleu X" first="Xavier" last="Leleu">Xavier Leleu</name><affiliation><nlm:aff id="aff5"><institution>Service d'Hématologie, Centre Hospitalier Universitaire (CHU)</institution>, Lille,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="De Becker, Ann" sort="De Becker, Ann" uniqKey="De Becker A" first="Ann" last="De Becker">Ann De Becker</name><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Van Camp, Ben" sort="Van Camp, Ben" uniqKey="Van Camp B" first="Ben" last="Van Camp">Ben Van Camp</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Croucher, Peter" sort="Croucher, Peter" uniqKey="Croucher P" first="Peter" last="Croucher">Peter Croucher</name><affiliation><nlm:aff id="aff6"><institution>Garvan Institute for Medical Research</institution>, Sydney,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Vanderkerken, Karin" sort="Vanderkerken, Karin" uniqKey="Vanderkerken K" first="Karin" last="Vanderkerken">Karin Vanderkerken</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Van Riet, Ivan" sort="Van Riet, Ivan" uniqKey="Van Riet I" first="Ivan" last="Van Riet">Ivan Van Riet</name><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23564084</idno><idno type="pmc">4002867</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002867</idno><idno type="RBID">PMC:4002867</idno><idno type="doi">10.1038/aps.2012.182</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000032</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000032</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells <italic>in vitro</italic> and bone formation <italic>in vivo</italic></title><author><name sortKey="Xu, Song" sort="Xu, Song" uniqKey="Xu S" first="Song" last="Xu">Song Xu</name><affiliation><nlm:aff id="aff1"><institution>Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital</institution>, Tianjin 300052,<country>China</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="De Veirman, Kim" sort="De Veirman, Kim" uniqKey="De Veirman K" first="Kim" last="De Veirman">Kim De Veirman</name><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Evans, Holly" sort="Evans, Holly" uniqKey="Evans H" first="Holly" last="Evans">Holly Evans</name><affiliation><nlm:aff id="aff4"><institution>Department of Human Metabolism, University of Sheffield Medical School</institution>, Sheffield,<country>UK</country></nlm:aff></affiliation></author><author><name sortKey="Santini, Gaia Cecilia" sort="Santini, Gaia Cecilia" uniqKey="Santini G" first="Gaia Cecilia" last="Santini">Gaia Cecilia Santini</name><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Vande Broek, Isabelle" sort="Vande Broek, Isabelle" uniqKey="Vande Broek I" first="Isabelle" last="Vande Broek">Isabelle Vande Broek</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Leleu, Xavier" sort="Leleu, Xavier" uniqKey="Leleu X" first="Xavier" last="Leleu">Xavier Leleu</name><affiliation><nlm:aff id="aff5"><institution>Service d'Hématologie, Centre Hospitalier Universitaire (CHU)</institution>, Lille,<country>France</country></nlm:aff></affiliation></author><author><name sortKey="De Becker, Ann" sort="De Becker, Ann" uniqKey="De Becker A" first="Ann" last="De Becker">Ann De Becker</name><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Van Camp, Ben" sort="Van Camp, Ben" uniqKey="Van Camp B" first="Ben" last="Van Camp">Ben Van Camp</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Croucher, Peter" sort="Croucher, Peter" uniqKey="Croucher P" first="Peter" last="Croucher">Peter Croucher</name><affiliation><nlm:aff id="aff6"><institution>Garvan Institute for Medical Research</institution>, Sydney,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Vanderkerken, Karin" sort="Vanderkerken, Karin" uniqKey="Vanderkerken K" first="Karin" last="Vanderkerken">Karin Vanderkerken</name><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Van Riet, Ivan" sort="Van Riet, Ivan" uniqKey="Van Riet I" first="Ivan" last="Van Riet">Ivan Van Riet</name><affiliation><nlm:aff id="aff2"><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></nlm:aff></affiliation></author></analytic><series><title level="j">Acta Pharmacologica Sinica</title><idno type="ISSN">1671-4083</idno><idno type="eISSN">1745-7254</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Aim:</title><p>Vorinostat, a histone deacetylase (HDAC) inhibitor currently in a clinical phase III trial for multiple myeloma (MM) patients, has been reported to cause bone loss. The purpose of this study was to test whether, and to what extent, vorinostat influences the osteogenic differentiation of mesenchymal stem cells (MSCs) <italic>in vitro</italic> and bone formation <italic>in vivo</italic>.</p></sec><sec><title>Methods:</title><p>Bone marrow-derived MSCs were prepared from both normal donors and MM patients. The MSCs were cultured in an osteogenic differentiation induction medium to induce osteogenic differentiation, which was evaluated by alkaline phosphatase (ALP) staining, Alizarin Red S staining and the mRNA expression of osteogenic markers. Naïve mice were administered vorinostat (100 mg/kg, ip) every other day for 3 weeks. After the mice were sacrificed, bone formation was assessed based on serum osteocalcin level and histomorphometric analysis.</p></sec><sec><title>Results:</title><p>Vorinostat inhibited the viability of hMSCs in a concentration-dependent manner (the IC<sub>50</sub> value was 15.57 μmol/L). The low concentration of vorinostat (1 μmol/L) did not significantly increase apoptosis in hMSCs, whereas pronounced apoptosis was observed following exposure to higher concentrations of vorinostat (10 and 50 μmol/L). In bone marrow-derived hMSCs from both normal donors and MM patients, vorinostat (1 μmol/L) significantly increased ALP activity, mRNA expression of osteogenic markers, and matrix mineralization. These effects were associated with upregulation of the bone-specifying transcription factor Runx2 and with the epigenetic alterations during normal hMSCs osteogenic differentiation. Importantly, the mice treated with vorinostat did not show any bone loss in response to the optimized treatment regimen.</p></sec><sec><title>Conclusion:</title><p>Vorinostat, known as a potent anti-myeloma drug, stimulates MSC osteogenesis <italic>in vitro</italic>. With the optimized treatment regimen, any decrease in bone formation was not observed <italic>in vivo</italic>.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Acta Pharmacol Sin</journal-id><journal-id journal-id-type="iso-abbrev">Acta Pharmacol. Sin</journal-id><journal-title-group><journal-title>Acta Pharmacologica Sinica</journal-title></journal-title-group><issn pub-type="ppub">1671-4083</issn><issn pub-type="epub">1745-7254</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23564084</article-id><article-id pub-id-type="pmc">4002867</article-id><article-id pub-id-type="pii">aps2012182</article-id><article-id pub-id-type="doi">10.1038/aps.2012.182</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells <italic>in vitro</italic> and bone formation <italic>in vivo</italic></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Song</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>De Veirman</surname><given-names>Kim</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Evans</surname><given-names>Holly</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Santini</surname><given-names>Gaia Cecilia</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Vande Broek</surname><given-names>Isabelle</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Leleu</surname><given-names>Xavier</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>De Becker</surname><given-names>Ann</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Van Camp</surname><given-names>Ben</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Croucher</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Vanderkerken</surname><given-names>Karin</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Van Riet</surname><given-names>Ivan</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="aff" rid="aff3">3</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><aff id="aff1"><label>1</label><institution>Department of Lung Cancer Surgery, Lung Cancer Institute, Tianjin Medical University General Hospital</institution>, Tianjin 300052,<country>China</country></aff><aff id="aff2"><label>2</label><institution>Stem Cell Laboratory-Division Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel)</institution>, Brussels,<country>Belgium</country></aff><aff id="aff3"><label>3</label><institution>Department of Hematology and Immunology-Vrije Universiteit Brussel (VUB), Myeloma Center Brussels</institution>, Brussels,<country>Belgium</country></aff><aff id="aff4"><label>4</label><institution>Department of Human Metabolism, University of Sheffield Medical School</institution>, Sheffield,<country>UK</country></aff><aff id="aff5"><label>5</label><institution>Service d'Hématologie, Centre Hospitalier Universitaire (CHU)</institution>, Lille,<country>France</country></aff><aff id="aff6"><label>6</label><institution>Garvan Institute for Medical Research</institution>, Sydney,<country>Australia</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label>E-mail <email>ivan.vanriet@uzbrussel.be</email></corresp></author-notes><pub-date pub-type="ppub"><month>05</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>08</day><month>04</month><year>2013</year></pub-date><volume>34</volume><issue>5</issue><fpage>699</fpage><lpage>709</lpage><history><date date-type="received"><day>21</day><month>08</month><year>2012</year></date><date date-type="accepted"><day>05</day><month>12</month><year>2012</year></date></history><permissions><copyright-statement>Copyright © 2013 CPS and SIMM</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>CPS and SIMM</copyright-holder></permissions><abstract><sec><title>Aim:</title><p>Vorinostat, a histone deacetylase (HDAC) inhibitor currently in a clinical phase III trial for multiple myeloma (MM) patients, has been reported to cause bone loss. The purpose of this study was to test whether, and to what extent, vorinostat influences the osteogenic differentiation of mesenchymal stem cells (MSCs) <italic>in vitro</italic> and bone formation <italic>in vivo</italic>.</p></sec><sec><title>Methods:</title><p>Bone marrow-derived MSCs were prepared from both normal donors and MM patients. The MSCs were cultured in an osteogenic differentiation induction medium to induce osteogenic differentiation, which was evaluated by alkaline phosphatase (ALP) staining, Alizarin Red S staining and the mRNA expression of osteogenic markers. Naïve mice were administered vorinostat (100 mg/kg, ip) every other day for 3 weeks. After the mice were sacrificed, bone formation was assessed based on serum osteocalcin level and histomorphometric analysis.</p></sec><sec><title>Results:</title><p>Vorinostat inhibited the viability of hMSCs in a concentration-dependent manner (the IC<sub>50</sub> value was 15.57 μmol/L). The low concentration of vorinostat (1 μmol/L) did not significantly increase apoptosis in hMSCs, whereas pronounced apoptosis was observed following exposure to higher concentrations of vorinostat (10 and 50 μmol/L). In bone marrow-derived hMSCs from both normal donors and MM patients, vorinostat (1 μmol/L) significantly increased ALP activity, mRNA expression of osteogenic markers, and matrix mineralization. These effects were associated with upregulation of the bone-specifying transcription factor Runx2 and with the epigenetic alterations during normal hMSCs osteogenic differentiation. Importantly, the mice treated with vorinostat did not show any bone loss in response to the optimized treatment regimen.</p></sec><sec><title>Conclusion:</title><p>Vorinostat, known as a potent anti-myeloma drug, stimulates MSC osteogenesis <italic>in vitro</italic>. With the optimized treatment regimen, any decrease in bone formation was not observed <italic>in vivo</italic>.</p></sec></abstract><kwd-group><kwd>histone deacetylase (HDAC)</kwd><kwd>vorinostat</kwd><kwd>mesenchymal stem cell</kwd><kwd>osteogenesis</kwd><kwd>alkaline phosphatase (ALP)</kwd><kwd>Runx2</kwd><kwd>osteocalcin</kwd><kwd>multiple myeloma</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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