Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells
Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) w...
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| Veröffentlicht in: | PloS one 2014, Vol.9 (2), p.e89525-e89525 |
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| creator | Montes de Oca, Addy Guerrero, Fatima Martinez-Moreno, Julio M Madueño, Juan A Herencia, Carmen Peralta, Alan Almaden, Yolanda Lopez, Ignacio Aguilera-Tejero, Escolastico Gundlach, Kristina Büchel, Janine Peter, Mirjam E Passlick-Deetjen, Jutta Rodriguez, Mariano Muñoz-Castañeda, Juan R |
| description | Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/β-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved. |
| doi_str_mv | 10.1371/journal.pone.0089525 |
| format | Article |
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This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/β-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0089525</identifier><identifier>PMID: 24586847</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Apoptosis ; beta Catenin - antagonists & inhibitors ; beta Catenin - genetics ; beta Catenin - metabolism ; Biocompatibility ; Biology ; Biomedical materials ; Boron Compounds - pharmacology ; Calcification ; Calcification (ectopic) ; Calcium ; Calcium content ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Cbfa-1 protein ; Cells, Cultured ; Dkk1 protein ; Extracellular Matrix Proteins - genetics ; Extracellular Matrix Proteins - metabolism ; Frizzled protein ; Gene expression ; Genetic transformation ; Homeostasis ; Humans ; Inhibition ; Kinases ; Lymphocytes B ; Magnesium ; Magnesium - pharmacology ; Matrix Gla Protein ; Medicine ; Muscle, Smooth, Vascular - cytology ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - metabolism ; Muscles ; Osteogenesis - drug effects ; Osteoprotegerin ; Osteoprotegerin - genetics ; Osteoprotegerin - metabolism ; Phosphates ; Protein Serine-Threonine Kinases ; Proteins ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; siRNA ; Smooth muscle ; Studies ; Transcription factors ; Transformation ; Transient receptor potential proteins ; Translocation ; Transport ; TRPM Cation Channels - antagonists & inhibitors ; TRPM Cation Channels - genetics ; TRPM Cation Channels - metabolism ; Vascular Calcification - drug therapy ; Vascular Calcification - metabolism ; Wnt protein ; Wnt Proteins - antagonists & inhibitors ; Wnt Proteins - genetics ; Wnt Proteins - metabolism ; β-Catenin</subject><ispartof>PloS one, 2014, Vol.9 (2), p.e89525-e89525</ispartof><rights>2014 Montes de Oca et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://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>2014 Montes de Oca et al 2014 Montes de Oca et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-93f9bf62c08c686ce197c2aa3097b788214150287f7aeb63bd1eb93bf265158d3</citedby><cites>FETCH-LOGICAL-c526t-93f9bf62c08c686ce197c2aa3097b788214150287f7aeb63bd1eb93bf265158d3</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/PMC3934896/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934896/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,4010,23847,27902,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24586847$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Genetos, Damian Christopher</contributor><creatorcontrib>Montes de Oca, Addy</creatorcontrib><creatorcontrib>Guerrero, Fatima</creatorcontrib><creatorcontrib>Martinez-Moreno, Julio M</creatorcontrib><creatorcontrib>Madueño, Juan A</creatorcontrib><creatorcontrib>Herencia, Carmen</creatorcontrib><creatorcontrib>Peralta, Alan</creatorcontrib><creatorcontrib>Almaden, Yolanda</creatorcontrib><creatorcontrib>Lopez, Ignacio</creatorcontrib><creatorcontrib>Aguilera-Tejero, Escolastico</creatorcontrib><creatorcontrib>Gundlach, Kristina</creatorcontrib><creatorcontrib>Büchel, Janine</creatorcontrib><creatorcontrib>Peter, Mirjam E</creatorcontrib><creatorcontrib>Passlick-Deetjen, Jutta</creatorcontrib><creatorcontrib>Rodriguez, Mariano</creatorcontrib><creatorcontrib>Muñoz-Castañeda, Juan R</creatorcontrib><title>Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/β-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved.</description><subject>Activation</subject><subject>Apoptosis</subject><subject>beta Catenin - antagonists & inhibitors</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Biocompatibility</subject><subject>Biology</subject><subject>Biomedical materials</subject><subject>Boron Compounds - pharmacology</subject><subject>Calcification</subject><subject>Calcification (ectopic)</subject><subject>Calcium</subject><subject>Calcium content</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Calcium-Binding Proteins - metabolism</subject><subject>Cbfa-1 protein</subject><subject>Cells, Cultured</subject><subject>Dkk1 protein</subject><subject>Extracellular Matrix Proteins - genetics</subject><subject>Extracellular Matrix Proteins - metabolism</subject><subject>Frizzled protein</subject><subject>Gene expression</subject><subject>Genetic transformation</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Kinases</subject><subject>Lymphocytes B</subject><subject>Magnesium</subject><subject>Magnesium - pharmacology</subject><subject>Matrix Gla Protein</subject><subject>Medicine</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscles</subject><subject>Osteogenesis - drug effects</subject><subject>Osteoprotegerin</subject><subject>Osteoprotegerin - genetics</subject><subject>Osteoprotegerin - metabolism</subject><subject>Phosphates</subject><subject>Protein Serine-Threonine Kinases</subject><subject>Proteins</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>siRNA</subject><subject>Smooth muscle</subject><subject>Studies</subject><subject>Transcription factors</subject><subject>Transformation</subject><subject>Transient receptor potential proteins</subject><subject>Translocation</subject><subject>Transport</subject><subject>TRPM Cation Channels - antagonists & inhibitors</subject><subject>TRPM Cation Channels - genetics</subject><subject>TRPM Cation Channels - metabolism</subject><subject>Vascular Calcification - drug therapy</subject><subject>Vascular Calcification - metabolism</subject><subject>Wnt protein</subject><subject>Wnt Proteins - antagonists & inhibitors</subject><subject>Wnt Proteins - genetics</subject><subject>Wnt Proteins - metabolism</subject><subject>β-Catenin</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUs2KFDEYbERx19E3EA148dKz-f-5CLL4s7DiRfEY0un0TIbuZEzSA_taPojPZMbpXXbFU0JSVV99RTXNSwTXiAh0sYtzCmZc72NwawilYpg9as6RIrjlGJLH9-5nzbOcdxAyIjl_2pxhyiSXVJw38xezCS77eQI-bH3nSwY_Qrn4_au1prjgAzC2-IMvN8CEHiR3cCm7DMrWgZiLi5sKsqAkE_IQ02SKjwHEARxMtvNoEshTjGULpjnb0QHrxjE_b54MZszuxXKumu8fP3y7_Nxef_10dfn-urUM89IqMqhu4NhCabnk1iElLDaGQCU6ISVGFDGIpRiEcR0nXY9cp0g3YM4Qkz1ZNa9PuvsxZr0klnWVEYxJVfNYNVcnRB_NTu-Tn0y60dF4_fchpo02qfjqXIteCdz3GELjaMeh7HsqFJNMooEJiqrWu2Xa3E2uty7UVMYHog9_gt_qTTxoogiVileBt4tAij9nl4uefD4GZoKLc_XNIEUcUoor9M0_0P9vR08om2LOyQ13ZhDUxxbdsvSxRXppUaW9ur_IHem2NuQPZRPIcg</recordid><startdate>2014</startdate><enddate>2014</enddate><creator>Montes de Oca, Addy</creator><creator>Guerrero, Fatima</creator><creator>Martinez-Moreno, Julio M</creator><creator>Madueño, Juan A</creator><creator>Herencia, Carmen</creator><creator>Peralta, Alan</creator><creator>Almaden, Yolanda</creator><creator>Lopez, Ignacio</creator><creator>Aguilera-Tejero, Escolastico</creator><creator>Gundlach, Kristina</creator><creator>Büchel, Janine</creator><creator>Peter, Mirjam E</creator><creator>Passlick-Deetjen, Jutta</creator><creator>Rodriguez, Mariano</creator><creator>Muñoz-Castañeda, Juan R</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>2014</creationdate><title>Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells</title><author>Montes de Oca, Addy ; Guerrero, Fatima ; Martinez-Moreno, Julio M ; Madueño, Juan A ; Herencia, Carmen ; Peralta, Alan ; Almaden, Yolanda ; Lopez, Ignacio ; Aguilera-Tejero, Escolastico ; Gundlach, Kristina ; Büchel, Janine ; Peter, Mirjam E ; Passlick-Deetjen, Jutta ; Rodriguez, Mariano ; Muñoz-Castañeda, Juan R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-93f9bf62c08c686ce197c2aa3097b788214150287f7aeb63bd1eb93bf265158d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Activation</topic><topic>Apoptosis</topic><topic>beta Catenin - antagonists & inhibitors</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Biocompatibility</topic><topic>Biology</topic><topic>Biomedical materials</topic><topic>Boron Compounds - pharmacology</topic><topic>Calcification</topic><topic>Calcification (ectopic)</topic><topic>Calcium</topic><topic>Calcium content</topic><topic>Calcium-Binding Proteins - genetics</topic><topic>Calcium-Binding Proteins - metabolism</topic><topic>Cbfa-1 protein</topic><topic>Cells, Cultured</topic><topic>Dkk1 protein</topic><topic>Extracellular Matrix Proteins - genetics</topic><topic>Extracellular Matrix Proteins - metabolism</topic><topic>Frizzled protein</topic><topic>Gene expression</topic><topic>Genetic transformation</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Kinases</topic><topic>Lymphocytes B</topic><topic>Magnesium</topic><topic>Magnesium - pharmacology</topic><topic>Matrix Gla Protein</topic><topic>Medicine</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscles</topic><topic>Osteogenesis - drug effects</topic><topic>Osteoprotegerin</topic><topic>Osteoprotegerin - genetics</topic><topic>Osteoprotegerin - metabolism</topic><topic>Phosphates</topic><topic>Protein Serine-Threonine Kinases</topic><topic>Proteins</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>siRNA</topic><topic>Smooth muscle</topic><topic>Studies</topic><topic>Transcription factors</topic><topic>Transformation</topic><topic>Transient receptor potential proteins</topic><topic>Translocation</topic><topic>Transport</topic><topic>TRPM Cation Channels - antagonists & inhibitors</topic><topic>TRPM Cation Channels - genetics</topic><topic>TRPM Cation Channels - metabolism</topic><topic>Vascular Calcification - drug therapy</topic><topic>Vascular Calcification - metabolism</topic><topic>Wnt protein</topic><topic>Wnt Proteins - antagonists & inhibitors</topic><topic>Wnt Proteins - genetics</topic><topic>Wnt Proteins - metabolism</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Montes de Oca, Addy</creatorcontrib><creatorcontrib>Guerrero, Fatima</creatorcontrib><creatorcontrib>Martinez-Moreno, Julio M</creatorcontrib><creatorcontrib>Madueño, Juan A</creatorcontrib><creatorcontrib>Herencia, Carmen</creatorcontrib><creatorcontrib>Peralta, Alan</creatorcontrib><creatorcontrib>Almaden, Yolanda</creatorcontrib><creatorcontrib>Lopez, Ignacio</creatorcontrib><creatorcontrib>Aguilera-Tejero, Escolastico</creatorcontrib><creatorcontrib>Gundlach, Kristina</creatorcontrib><creatorcontrib>Büchel, Janine</creatorcontrib><creatorcontrib>Peter, Mirjam E</creatorcontrib><creatorcontrib>Passlick-Deetjen, Jutta</creatorcontrib><creatorcontrib>Rodriguez, Mariano</creatorcontrib><creatorcontrib>Muñoz-Castañeda, Juan R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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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>Montes de Oca, Addy</au><au>Guerrero, Fatima</au><au>Martinez-Moreno, Julio M</au><au>Madueño, Juan A</au><au>Herencia, Carmen</au><au>Peralta, Alan</au><au>Almaden, Yolanda</au><au>Lopez, Ignacio</au><au>Aguilera-Tejero, Escolastico</au><au>Gundlach, Kristina</au><au>Büchel, Janine</au><au>Peter, Mirjam E</au><au>Passlick-Deetjen, Jutta</au><au>Rodriguez, Mariano</au><au>Muñoz-Castañeda, Juan R</au><au>Genetos, Damian Christopher</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014</date><risdate>2014</risdate><volume>9</volume><issue>2</issue><spage>e89525</spage><epage>e89525</epage><pages>e89525-e89525</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/β-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24586847</pmid><doi>10.1371/journal.pone.0089525</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014, Vol.9 (2), p.e89525-e89525 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1977558905 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Activation Apoptosis beta Catenin - antagonists & inhibitors beta Catenin - genetics beta Catenin - metabolism Biocompatibility Biology Biomedical materials Boron Compounds - pharmacology Calcification Calcification (ectopic) Calcium Calcium content Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Cbfa-1 protein Cells, Cultured Dkk1 protein Extracellular Matrix Proteins - genetics Extracellular Matrix Proteins - metabolism Frizzled protein Gene expression Genetic transformation Homeostasis Humans Inhibition Kinases Lymphocytes B Magnesium Magnesium - pharmacology Matrix Gla Protein Medicine Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - metabolism Muscles Osteogenesis - drug effects Osteoprotegerin Osteoprotegerin - genetics Osteoprotegerin - metabolism Phosphates Protein Serine-Threonine Kinases Proteins Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics Signal transduction Signal Transduction - drug effects Signaling siRNA Smooth muscle Studies Transcription factors Transformation Transient receptor potential proteins Translocation Transport TRPM Cation Channels - antagonists & inhibitors TRPM Cation Channels - genetics TRPM Cation Channels - metabolism Vascular Calcification - drug therapy Vascular Calcification - metabolism Wnt protein Wnt Proteins - antagonists & inhibitors Wnt Proteins - genetics Wnt Proteins - metabolism β-Catenin |
| title | Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells |
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