Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST
Bone loss induced by hypoxia is associated with various pathophysiological conditions, however, little is known about the effects of hypoxia and related signaling pathways on osteoblast differentiation and bone formation. Because bone marrow-derived mesenchymal stem cells (MSCs) survive under hypoxi...
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| Veröffentlicht in: | PloS one 2011-09, Vol.6 (9), p.e23965-e23965 |
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| creator | Yang, Der-Chih Yang, Muh-Hwa Tsai, Chih-Chien Huang, Tung-Fu Chen, Yau-Hung Hung, Shih-Chieh |
| description | Bone loss induced by hypoxia is associated with various pathophysiological conditions, however, little is known about the effects of hypoxia and related signaling pathways on osteoblast differentiation and bone formation. Because bone marrow-derived mesenchymal stem cells (MSCs) survive under hypoxic conditions and readily differentiate into osteoblasts by standard induction protocols, they are a good in vitro model to study the effects of hypoxia on osteoblast differentiation.
Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. Suppression of type 1 RUNX2 by TWIST under hypoxia further inhibited the expression of BMP2, type 2 RUNX2 and downstream targets of RUNX2 in MSCs.
Our findings point to the important role of hypoxia-mediated signalling in osteogenic differentiation in MSCs through direct regulation of RUNX2 by TWIST, and provide a method for modifying MSC osteogenesis upon application of these cells in fracture healing and bone reconstruction. |
| doi_str_mv | 10.1371/journal.pone.0023965 |
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Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. Suppression of type 1 RUNX2 by TWIST under hypoxia further inhibited the expression of BMP2, type 2 RUNX2 and downstream targets of RUNX2 in MSCs.
Our findings point to the important role of hypoxia-mediated signalling in osteogenic differentiation in MSCs through direct regulation of RUNX2 by TWIST, and provide a method for modifying MSC osteogenesis upon application of these cells in fracture healing and bone reconstruction.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0023965</identifier><identifier>PMID: 21931630</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Angiogenesis ; Arthritis ; Biocompatibility ; Biology ; Biomedical materials ; Bone growth ; Bone healing ; Bone loss ; Bone marrow ; Bone morphogenetic protein 2 ; Bone morphogenetic proteins ; Cbfa-1 protein ; Cell Differentiation - genetics ; Cell Hypoxia - genetics ; Clinical medicine ; Core Binding Factor Alpha 1 Subunit - genetics ; Differentiation ; Down-Regulation - genetics ; Education ; Fibroblasts ; Growth factors ; Hematology ; Hospitals ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Medical research ; Medicine ; Mesenchymal stem cells ; Mesenchymal Stromal Cells - cytology ; Mesenchymal Stromal Cells - metabolism ; Mesenchyme ; Metastasis ; Mineralization ; Osteoblastogenesis ; Osteoblasts ; Osteogenesis ; Osteogenesis - genetics ; Promoter Regions, Genetic - genetics ; Rodents ; Signal transduction ; Signaling ; Stem cells ; Transcription ; Transcription factors ; Twist-Related Protein 1 - metabolism</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e23965-e23965</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Yang et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-70ccb4672c847815b0cff9dd584a3e1c4fc50e655935d0c281b2b0bb4df5c3fc3</citedby><cites>FETCH-LOGICAL-c691t-70ccb4672c847815b0cff9dd584a3e1c4fc50e655935d0c281b2b0bb4df5c3fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170288/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170288/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2101,2927,23865,27923,27924,53790,53792,79471,79472</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21931630$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Milstone, David S.</contributor><creatorcontrib>Yang, Der-Chih</creatorcontrib><creatorcontrib>Yang, Muh-Hwa</creatorcontrib><creatorcontrib>Tsai, Chih-Chien</creatorcontrib><creatorcontrib>Huang, Tung-Fu</creatorcontrib><creatorcontrib>Chen, Yau-Hung</creatorcontrib><creatorcontrib>Hung, Shih-Chieh</creatorcontrib><title>Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Bone loss induced by hypoxia is associated with various pathophysiological conditions, however, little is known about the effects of hypoxia and related signaling pathways on osteoblast differentiation and bone formation. Because bone marrow-derived mesenchymal stem cells (MSCs) survive under hypoxic conditions and readily differentiate into osteoblasts by standard induction protocols, they are a good in vitro model to study the effects of hypoxia on osteoblast differentiation.
Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. Suppression of type 1 RUNX2 by TWIST under hypoxia further inhibited the expression of BMP2, type 2 RUNX2 and downstream targets of RUNX2 in MSCs.
Our findings point to the important role of hypoxia-mediated signalling in osteogenic differentiation in MSCs through direct regulation of RUNX2 by TWIST, and provide a method for modifying MSC osteogenesis upon application of these cells in fracture healing and bone reconstruction.</description><subject>Analysis</subject><subject>Angiogenesis</subject><subject>Arthritis</subject><subject>Biocompatibility</subject><subject>Biology</subject><subject>Biomedical materials</subject><subject>Bone growth</subject><subject>Bone healing</subject><subject>Bone loss</subject><subject>Bone marrow</subject><subject>Bone morphogenetic protein 2</subject><subject>Bone morphogenetic proteins</subject><subject>Cbfa-1 protein</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Hypoxia - genetics</subject><subject>Clinical medicine</subject><subject>Core Binding Factor Alpha 1 Subunit - genetics</subject><subject>Differentiation</subject><subject>Down-Regulation - genetics</subject><subject>Education</subject><subject>Fibroblasts</subject><subject>Growth factors</subject><subject>Hematology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Der-Chih</au><au>Yang, Muh-Hwa</au><au>Tsai, Chih-Chien</au><au>Huang, Tung-Fu</au><au>Chen, Yau-Hung</au><au>Hung, Shih-Chieh</au><au>Milstone, David S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-09-09</date><risdate>2011</risdate><volume>6</volume><issue>9</issue><spage>e23965</spage><epage>e23965</epage><pages>e23965-e23965</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Bone loss induced by hypoxia is associated with various pathophysiological conditions, however, little is known about the effects of hypoxia and related signaling pathways on osteoblast differentiation and bone formation. Because bone marrow-derived mesenchymal stem cells (MSCs) survive under hypoxic conditions and readily differentiate into osteoblasts by standard induction protocols, they are a good in vitro model to study the effects of hypoxia on osteoblast differentiation.
Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. Suppression of type 1 RUNX2 by TWIST under hypoxia further inhibited the expression of BMP2, type 2 RUNX2 and downstream targets of RUNX2 in MSCs.
Our findings point to the important role of hypoxia-mediated signalling in osteogenic differentiation in MSCs through direct regulation of RUNX2 by TWIST, and provide a method for modifying MSC osteogenesis upon application of these cells in fracture healing and bone reconstruction.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21931630</pmid><doi>10.1371/journal.pone.0023965</doi><tpages>e23965</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Analysis Angiogenesis Arthritis Biocompatibility Biology Biomedical materials Bone growth Bone healing Bone loss Bone marrow Bone morphogenetic protein 2 Bone morphogenetic proteins Cbfa-1 protein Cell Differentiation - genetics Cell Hypoxia - genetics Clinical medicine Core Binding Factor Alpha 1 Subunit - genetics Differentiation Down-Regulation - genetics Education Fibroblasts Growth factors Hematology Hospitals Humans Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Medical research Medicine Mesenchymal stem cells Mesenchymal Stromal Cells - cytology Mesenchymal Stromal Cells - metabolism Mesenchyme Metastasis Mineralization Osteoblastogenesis Osteoblasts Osteogenesis Osteogenesis - genetics Promoter Regions, Genetic - genetics Rodents Signal transduction Signaling Stem cells Transcription Transcription factors Twist-Related Protein 1 - metabolism |
| title | Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST |
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