Sildenafil accelerates fracture healing in mice
Identifieur interne : 001815 ( Istex/Corpus ); précédent : 001814; suivant : 001816Sildenafil accelerates fracture healing in mice
Auteurs : Tina Histing ; Kerstin Marciniak ; Claudia Scheuer ; Patric Garcia ; Joerg H. Holstein ; Moritz Klein ; Romano Matthys ; Tim Pohlemann ; Michael D. MengerSource :
- Journal of Orthopaedic Research [ 0736-0266 ] ; 2011-06.
English descriptors
- KwdEn :
- Teeft :
- Angiogenesis, Angiogenic, Angiogenic response, Biomechanical, Biomechanical analysis, Biomechanical stiffness, Black columns, Body weight, Bone formation, Bone healing, Bone miner, Brous tissue, Callus, Callus area, Callus tissue, Cartilage, Cartilaginous callus callus area, Cartilaginous tissue, Enos, Enos expression, Equivalent amounts, Femur, Fracture, Fracture healing, Fracture repair, Growth factor, Growth factors, Healing, Healthcare amersham, Histing, Histomorphometric analysis, Histomorphometrical analysis, Hypercholesterolemic apolipoprotein mice, Important role, Individual animals, Intramedullary canal, June, Nitric oxide, Orthopaedic, Orthopaedic research june, Orthopaedic research society, Osseous fracture, Osteoblast, Potent stimulator, Present study, Protein expression, Radiological, Radiological analysis, Rankl, Santa cruz biotechnology, Stiffness, Total callus area, Vegf, Western blot analysis, White columns, Whole protein extracts, Wiley periodicals.
Abstract
Sildenafil, a cyclic guanosine monophosphate (cGMP)‐dependent phospodiesterase‐5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro‐angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro‐angiogenic and osteogenic cysteine‐rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61‐associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873
Url:
DOI: 10.1002/jor.21324
Links to Exploration step
ISTEX:E84718362978E0D37B63C4D9965BE2AA92990E0ALe document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Sildenafil accelerates fracture healing in mice</title><author><name sortKey="Histing, Tina" sort="Histing, Tina" uniqKey="Histing T" first="Tina" last="Histing">Tina Histing</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany, T: 49‐6841‐16‐31502; F: 49‐6841‐16‐31503.</mods:affiliation></affiliation></author><author><name sortKey="Marciniak, Kerstin" sort="Marciniak, Kerstin" uniqKey="Marciniak K" first="Kerstin" last="Marciniak">Kerstin Marciniak</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Scheuer, Claudia" sort="Scheuer, Claudia" uniqKey="Scheuer C" first="Claudia" last="Scheuer">Claudia Scheuer</name><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Garcia, Patric" sort="Garcia, Patric" uniqKey="Garcia P" first="Patric" last="Garcia">Patric Garcia</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Holstein, Joerg H" sort="Holstein, Joerg H" uniqKey="Holstein J" first="Joerg H." last="Holstein">Joerg H. Holstein</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Klein, Moritz" sort="Klein, Moritz" uniqKey="Klein M" first="Moritz" last="Klein">Moritz Klein</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Matthys, Romano" sort="Matthys, Romano" uniqKey="Matthys R" first="Romano" last="Matthys">Romano Matthys</name><affiliation><mods:affiliation>AO Development Institute, Davos, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Pohlemann, Tim" sort="Pohlemann, Tim" uniqKey="Pohlemann T" first="Tim" last="Pohlemann">Tim Pohlemann</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Menger, Michael D" sort="Menger, Michael D" uniqKey="Menger M" first="Michael D." last="Menger">Michael D. Menger</name><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:E84718362978E0D37B63C4D9965BE2AA92990E0A</idno><date when="2011" year="2011">2011</date><idno type="doi">10.1002/jor.21324</idno><idno type="url">https://api.istex.fr/document/E84718362978E0D37B63C4D9965BE2AA92990E0A/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001815</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001815</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Sildenafil accelerates fracture healing in mice</title><author><name sortKey="Histing, Tina" sort="Histing, Tina" uniqKey="Histing T" first="Tina" last="Histing">Tina Histing</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany, T: 49‐6841‐16‐31502; F: 49‐6841‐16‐31503.</mods:affiliation></affiliation></author><author><name sortKey="Marciniak, Kerstin" sort="Marciniak, Kerstin" uniqKey="Marciniak K" first="Kerstin" last="Marciniak">Kerstin Marciniak</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Scheuer, Claudia" sort="Scheuer, Claudia" uniqKey="Scheuer C" first="Claudia" last="Scheuer">Claudia Scheuer</name><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Garcia, Patric" sort="Garcia, Patric" uniqKey="Garcia P" first="Patric" last="Garcia">Patric Garcia</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Holstein, Joerg H" sort="Holstein, Joerg H" uniqKey="Holstein J" first="Joerg H." last="Holstein">Joerg H. Holstein</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Klein, Moritz" sort="Klein, Moritz" uniqKey="Klein M" first="Moritz" last="Klein">Moritz Klein</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Matthys, Romano" sort="Matthys, Romano" uniqKey="Matthys R" first="Romano" last="Matthys">Romano Matthys</name><affiliation><mods:affiliation>AO Development Institute, Davos, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Pohlemann, Tim" sort="Pohlemann, Tim" uniqKey="Pohlemann T" first="Tim" last="Pohlemann">Tim Pohlemann</name><affiliation><mods:affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation></author><author><name sortKey="Menger, Michael D" sort="Menger, Michael D" uniqKey="Menger M" first="Michael D." last="Menger">Michael D. Menger</name><affiliation><mods:affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Orthopaedic Research</title><title level="j" type="abbrev">J. Orthop. Res.</title><idno type="ISSN">0736-0266</idno><idno type="eISSN">1554-527X</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-06">2011-06</date><biblScope unit="volume">29</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="867">867</biblScope><biblScope unit="page" to="873">873</biblScope></imprint><idno type="ISSN">0736-0266</idno></series><idno type="istex">E84718362978E0D37B63C4D9965BE2AA92990E0A</idno><idno type="DOI">10.1002/jor.21324</idno><idno type="ArticleID">JOR21324</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0736-0266</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>CYR61</term><term>biomechanics</term><term>bone formation</term><term>fracture healing</term><term>mice</term><term>sildenafil</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Angiogenesis</term><term>Angiogenic</term><term>Angiogenic response</term><term>Biomechanical</term><term>Biomechanical analysis</term><term>Biomechanical stiffness</term><term>Black columns</term><term>Body weight</term><term>Bone formation</term><term>Bone healing</term><term>Bone miner</term><term>Brous tissue</term><term>Callus</term><term>Callus area</term><term>Callus tissue</term><term>Cartilage</term><term>Cartilaginous callus callus area</term><term>Cartilaginous tissue</term><term>Enos</term><term>Enos expression</term><term>Equivalent amounts</term><term>Femur</term><term>Fracture</term><term>Fracture healing</term><term>Fracture repair</term><term>Growth factor</term><term>Growth factors</term><term>Healing</term><term>Healthcare amersham</term><term>Histing</term><term>Histomorphometric analysis</term><term>Histomorphometrical analysis</term><term>Hypercholesterolemic apolipoprotein mice</term><term>Important role</term><term>Individual animals</term><term>Intramedullary canal</term><term>June</term><term>Nitric oxide</term><term>Orthopaedic</term><term>Orthopaedic research june</term><term>Orthopaedic research society</term><term>Osseous fracture</term><term>Osteoblast</term><term>Potent stimulator</term><term>Present study</term><term>Protein expression</term><term>Radiological</term><term>Radiological analysis</term><term>Rankl</term><term>Santa cruz biotechnology</term><term>Stiffness</term><term>Total callus area</term><term>Vegf</term><term>Western blot analysis</term><term>White columns</term><term>Whole protein extracts</term><term>Wiley periodicals</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Sildenafil, a cyclic guanosine monophosphate (cGMP)‐dependent phospodiesterase‐5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro‐angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro‐angiogenic and osteogenic cysteine‐rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61‐associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>callus</json:string><json:string>fracture healing</json:string><json:string>fracture</json:string><json:string>vegf</json:string><json:string>biomechanical</json:string><json:string>angiogenic</json:string><json:string>femur</json:string><json:string>radiological</json:string><json:string>present study</json:string><json:string>orthopaedic</json:string><json:string>angiogenesis</json:string><json:string>histing</json:string><json:string>orthopaedic research june</json:string><json:string>osteoblast</json:string><json:string>rankl</json:string><json:string>june</json:string><json:string>callus tissue</json:string><json:string>bone healing</json:string><json:string>western blot analysis</json:string><json:string>bone formation</json:string><json:string>white columns</json:string><json:string>black columns</json:string><json:string>healing</json:string><json:string>enos</json:string><json:string>stiffness</json:string><json:string>growth factors</json:string><json:string>histomorphometric analysis</json:string><json:string>santa cruz biotechnology</json:string><json:string>callus area</json:string><json:string>important role</json:string><json:string>enos expression</json:string><json:string>biomechanical analysis</json:string><json:string>biomechanical stiffness</json:string><json:string>bone miner</json:string><json:string>total callus area</json:string><json:string>cartilaginous callus callus area</json:string><json:string>cartilaginous tissue</json:string><json:string>brous tissue</json:string><json:string>equivalent amounts</json:string><json:string>whole protein extracts</json:string><json:string>body weight</json:string><json:string>histomorphometrical analysis</json:string><json:string>orthopaedic research society</json:string><json:string>healthcare amersham</json:string><json:string>protein expression</json:string><json:string>wiley periodicals</json:string><json:string>potent stimulator</json:string><json:string>intramedullary canal</json:string><json:string>radiological analysis</json:string><json:string>osseous fracture</json:string><json:string>fracture repair</json:string><json:string>individual animals</json:string><json:string>angiogenic response</json:string><json:string>nitric oxide</json:string><json:string>hypercholesterolemic apolipoprotein mice</json:string><json:string>growth factor</json:string><json:string>cartilage</json:string></teeft></keywords><author><json:item><name>Tina Histing</name><affiliations><json:string>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</json:string><json:string>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</json:string><json:string>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany, T: 49‐6841‐16‐31502; F: 49‐6841‐16‐31503.</json:string></affiliations></json:item><json:item><name>Kerstin Marciniak</name><affiliations><json:string>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</json:string><json:string>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</json:string></affiliations></json:item><json:item><name>Claudia Scheuer</name><affiliations><json:string>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</json:string><json:string>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</json:string></affiliations></json:item><json:item><name>Patric Garcia</name><affiliations><json:string>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</json:string><json:string>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</json:string></affiliations></json:item><json:item><name>Joerg H. Holstein</name><affiliations><json:string>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</json:string><json:string>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</json:string></affiliations></json:item><json:item><name>Moritz Klein</name><affiliations><json:string>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</json:string><json:string>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</json:string></affiliations></json:item><json:item><name>Romano Matthys</name><affiliations><json:string>AO Development Institute, Davos, Switzerland</json:string></affiliations></json:item><json:item><name>Tim Pohlemann</name><affiliations><json:string>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</json:string><json:string>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</json:string></affiliations></json:item><json:item><name>Michael D. Menger</name><affiliations><json:string>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</json:string><json:string>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>sildenafil</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>mice</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>fracture healing</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>bone formation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CYR61</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>biomechanics</value></json:item></subject><articleId><json:string>JOR21324</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Sildenafil, a cyclic guanosine monophosphate (cGMP)‐dependent phospodiesterase‐5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro‐angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro‐angiogenic and osteogenic cysteine‐rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61‐associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873</abstract><qualityIndicators><score>6.341</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1556</abstractCharCount><pdfWordCount>3857</pdfWordCount><pdfCharCount>25581</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>207</abstractWordCount></qualityIndicators><title>Sildenafil accelerates fracture healing in mice</title><genre><json:string>article</json:string></genre><host><title>Journal of Orthopaedic Research</title><language><json:string>unknown</json:string></language><doi><json:string>10.1002/(ISSN)1554-527X</json:string></doi><issn><json:string>0736-0266</json:string></issn><eissn><json:string>1554-527X</json:string></eissn><publisherId><json:string>JOR</json:string></publisherId><volume>29</volume><issue>6</issue><pages><first>867</first><last>873</last><total>7</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Research Article</value></json:item></subject></host><categories><wos><json:string>science</json:string><json:string>orthopedics</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>orthopedics</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string></inist></categories><publicationDate>2011</publicationDate><copyrightDate>2011</copyrightDate><doi><json:string>10.1002/jor.21324</json:string></doi><id>E84718362978E0D37B63C4D9965BE2AA92990E0A</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/E84718362978E0D37B63C4D9965BE2AA92990E0A/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/E84718362978E0D37B63C4D9965BE2AA92990E0A/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/E84718362978E0D37B63C4D9965BE2AA92990E0A/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Sildenafil accelerates fracture healing in mice</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>Copyright © 2011 Orthopaedic Research Society</p></availability><date>2011</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Sildenafil accelerates fracture healing in mice</title><author xml:id="author-1"><persName><forename type="first">Tina</forename><surname>Histing</surname></persName><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany, T: 49‐6841‐16‐31502; F: 49‐6841‐16‐31503.</affiliation></author><author xml:id="author-2"><persName><forename type="first">Kerstin</forename><surname>Marciniak</surname></persName><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation></author><author xml:id="author-3"><persName><forename type="first">Claudia</forename><surname>Scheuer</surname></persName><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><affiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</affiliation></author><author xml:id="author-4"><persName><forename type="first">Patric</forename><surname>Garcia</surname></persName><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation></author><author xml:id="author-5"><persName><forename type="first">Joerg H.</forename><surname>Holstein</surname></persName><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation></author><author xml:id="author-6"><persName><forename type="first">Moritz</forename><surname>Klein</surname></persName><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation></author><author xml:id="author-7"><persName><forename type="first">Romano</forename><surname>Matthys</surname></persName><affiliation>AO Development Institute, Davos, Switzerland</affiliation></author><author xml:id="author-8"><persName><forename type="first">Tim</forename><surname>Pohlemann</surname></persName><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation></author><author xml:id="author-9"><persName><forename type="first">Michael D.</forename><surname>Menger</surname></persName><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><affiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</affiliation></author></analytic><monogr><title level="j">Journal of Orthopaedic Research</title><title level="j" type="abbrev">J. Orthop. Res.</title><idno type="pISSN">0736-0266</idno><idno type="eISSN">1554-527X</idno><idno type="DOI">10.1002/(ISSN)1554-527X</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-06"></date><biblScope unit="volume">29</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="867">867</biblScope><biblScope unit="page" to="873">873</biblScope></imprint></monogr><idno type="istex">E84718362978E0D37B63C4D9965BE2AA92990E0A</idno><idno type="DOI">10.1002/jor.21324</idno><idno type="ArticleID">JOR21324</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2011</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Sildenafil, a cyclic guanosine monophosphate (cGMP)‐dependent phospodiesterase‐5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro‐angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro‐angiogenic and osteogenic cysteine‐rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61‐associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>keywords</head><item><term>sildenafil</term></item><item><term>mice</term></item><item><term>fracture healing</term></item><item><term>bone formation</term></item><item><term>CYR61</term></item><item><term>biomechanics</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2010-07-29">Received</change><change when="2010-11-08">Registration</change><change when="2011-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/E84718362978E0D37B63C4D9965BE2AA92990E0A/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1554-527X</doi><issn type="print">0736-0266</issn><issn type="electronic">1554-527X</issn><idGroup><id type="product" value="JOR"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="JOURNAL OF ORTHOPAEDIC RESEARCH">Journal of Orthopaedic Research</title><title type="short">J. Orthop. Res.</title></titleGroup></publicationMeta><publicationMeta level="part" position="60"><doi origin="wiley" registered="yes">10.1002/jor.v29.6</doi><numberingGroup><numbering type="journalVolume" number="29">29</numbering><numbering type="journalIssue">6</numbering></numberingGroup><coverDate startDate="2011-06">June 2011</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="120" status="forIssue"><doi origin="wiley" registered="yes">10.1002/jor.21324</doi><idGroup><id type="unit" value="JOR21324"></id></idGroup><countGroup><count type="pageTotal" number="7"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2011 Orthopaedic Research Society</copyright><eventGroup><event type="manuscriptReceived" date="2010-07-29"></event><event type="manuscriptAccepted" date="2010-11-08"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.4.9 mode:FullText" date="2011-05-27"></event><event type="publishedOnlineEarlyUnpaginated" date="2011-01-18"></event><event type="publishedOnlineFinalForm" date="2011-04-21"></event><event type="firstOnline" date="2011-01-18"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-31"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-30"></event></eventGroup><numberingGroup><numbering type="pageFirst">867</numbering><numbering type="pageLast">873</numbering></numberingGroup><correspondenceTo>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany, T: 49‐6841‐16‐31502; F: 49‐6841‐16‐31503.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:JOR.JOR21324.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="5"></count><count type="tableTotal" number="1"></count><count type="referenceTotal" number="32"></count><count type="wordTotal" number="4153"></count></countGroup><titleGroup><title type="main" xml:lang="en">Sildenafil accelerates fracture healing in mice</title><title type="short" xml:lang="en">SILDENAFIL ACCELERATES FRACTURE HEALING</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2" corresponding="yes"><personName><givenNames>Tina</givenNames><familyName>Histing</familyName></personName><contactDetails><email>tina.histing@uks.eu</email></contactDetails></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Kerstin</givenNames><familyName>Marciniak</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af2 #af3"><personName><givenNames>Claudia</givenNames><familyName>Scheuer</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Patric</givenNames><familyName>Garcia</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Joerg H.</givenNames><familyName>Holstein</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Moritz</givenNames><familyName>Klein</familyName></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Romano</givenNames><familyName>Matthys</familyName></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Tim</givenNames><familyName>Pohlemann</familyName></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af2 #af3"><personName><givenNames>Michael D.</givenNames><familyName>Menger</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="DE" type="organization"><unparsedAffiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="DE" type="organization"><unparsedAffiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="DE" type="organization"><unparsedAffiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="CH" type="organization"><unparsedAffiliation>AO Development Institute, Davos, Switzerland</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">sildenafil</keyword><keyword xml:id="kwd2">mice</keyword><keyword xml:id="kwd3">fracture healing</keyword><keyword xml:id="kwd4">bone formation</keyword><keyword xml:id="kwd5">CYR61</keyword><keyword xml:id="kwd6">biomechanics</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Sildenafil, a cyclic guanosine monophosphate (cGMP)‐dependent phospodiesterase‐5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro‐angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (<i>n</i> = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro‐angiogenic and osteogenic cysteine‐rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61‐associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Sildenafil accelerates fracture healing in mice</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>SILDENAFIL ACCELERATES FRACTURE HEALING</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Sildenafil accelerates fracture healing in mice</title></titleInfo><name type="personal"><namePart type="given">Tina</namePart><namePart type="family">Histing</namePart><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany, T: 49‐6841‐16‐31502; F: 49‐6841‐16‐31503.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kerstin</namePart><namePart type="family">Marciniak</namePart><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Claudia</namePart><namePart type="family">Scheuer</namePart><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><affiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patric</namePart><namePart type="family">Garcia</namePart><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Joerg H.</namePart><namePart type="family">Holstein</namePart><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Moritz</namePart><namePart type="family">Klein</namePart><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Romano</namePart><namePart type="family">Matthys</namePart><affiliation>AO Development Institute, Davos, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tim</namePart><namePart type="family">Pohlemann</namePart><affiliation>Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, D‐66421 Homburg/Saar, Germany</affiliation><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael D.</namePart><namePart type="family">Menger</namePart><affiliation>CRC Homburg (Collaborative Research Center, AO Foundation, Switzerland), Homburg/Saar, Germany</affiliation><affiliation>Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2011-06</dateIssued><dateCaptured encoding="w3cdtf">2010-07-29</dateCaptured><dateValid encoding="w3cdtf">2010-11-08</dateValid><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">5</extent><extent unit="tables">1</extent><extent unit="references">32</extent><extent unit="words">4153</extent></physicalDescription><abstract lang="en">Sildenafil, a cyclic guanosine monophosphate (cGMP)‐dependent phospodiesterase‐5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro‐angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro‐angiogenic and osteogenic cysteine‐rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61‐associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873</abstract><subject lang="en"><genre>keywords</genre><topic>sildenafil</topic><topic>mice</topic><topic>fracture healing</topic><topic>bone formation</topic><topic>CYR61</topic><topic>biomechanics</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Orthopaedic Research</title></titleInfo><titleInfo type="abbreviated"><title>J. Orthop. Res.</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0736-0266</identifier><identifier type="eISSN">1554-527X</identifier><identifier type="DOI">10.1002/(ISSN)1554-527X</identifier><identifier type="PublisherID">JOR</identifier><part><date>2011</date><detail type="volume"><caption>vol.</caption><number>29</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>867</start><end>873</end><total>7</total></extent></part></relatedItem><identifier type="istex">E84718362978E0D37B63C4D9965BE2AA92990E0A</identifier><identifier type="DOI">10.1002/jor.21324</identifier><identifier type="ArticleID">JOR21324</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2011 Orthopaedic Research Society</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sarre/explor/MusicSarreV3/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 001815 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 001815 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sarre
|area= MusicSarreV3
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:E84718362978E0D37B63C4D9965BE2AA92990E0A
|texte= Sildenafil accelerates fracture healing in mice
}}
| This area was generated with Dilib version V0.6.33. |  |