{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:46:06Z","timestamp":1792673166158,"version":"4.5.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2005,11,1]],"date-time":"2005-11-01T00:00:00Z","timestamp":1130803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We studied the interaction between VEGF and BMP2 during bone formation and bone healing. Results indicate that VEGF antagonist inhibited BMP2-elicited bone formation, whereas the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing through modulation of angiogenesis.<\/jats:p>\n               <jats:p>Introduction: Angiogenesis is closely associated with bone formation during normal bone development and is important for the bone formation elicited by BMP4. However, it remains unknown whether vascular endothelial growth factor (VEGF) also interacts with other BMPs, especially BMP2, in bone formation and bone healing.<\/jats:p>\n               <jats:p>Materials and Methods: For this study, mouse muscle-derived stem cells were transduced to express BMP2, VEGF, or VEGF antagonist (sFlt1). We studied the angiogenic process during endochondral bone formation elicited by BMP2, a prototypical osteogenic BMP. Using radiographic and histologic analyses, we also evaluated the interaction between VEGF and BMP2 during bone formation and bone healing.<\/jats:p>\n               <jats:p>Results: Our results indicate that BMP2-elicited bone formation comprises two phases of angiogenesis, with an early phase occurring before the appearance of hypertrophic cartilage, followed by a late phase coupled with the appearance of hypertrophic cartilage. Our finding that the administration of sFlt1, a specific antagonist of VEGF, significantly inhibited BMP2-induced bone formation and the associated angiogenesis indicates that endogenous VEGF activity is important for bone formation. Furthermore, we found that the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing by improving angiogenesis, which in turn led to accelerated cartilage resorption and enhanced mineralized bone formation. Our findings also indicate that the ratio between VEGF and BMP2 influences their synergistic interaction, with a higher proportion of VEGF leading to decreased synergism. Our study also revealed unique VEGF-BMP2 interactions that differ from the VEGF-BMP4 interactions that we have described previously.<\/jats:p>\n               <jats:p>Conclusions: This study, along with previously published work, shows that VEGF interacts synergistically with both BMP4 and BMP2 but elicits substantially different effects with these two BMPs.<\/jats:p>","DOI":"10.1359\/jbmr.050708","type":"journal-article","created":{"date-parts":[[2006,4,27]],"date-time":"2006-04-27T07:27:46Z","timestamp":1146122866000},"page":"2017-2027","source":"Crossref","is-referenced-by-count":363,"title":["VEGF Improves, Whereas sFlt1 Inhibits, BMP2-Induced Bone Formation and Bone Healing Through Modulation of Angiogenesis"],"prefix":"10.1093","volume":"20","author":[{"given":"Hairong","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, West Penn Hospital, Pittsburgh, Pennsylvania, USA"},{"name":"Growth and Development Laboratory, Children's Hospital of Pittsburgh and Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvydas","family":"Usas","sequence":"additional","affiliation":[{"name":"Growth and Development Laboratory, Children's Hospital of Pittsburgh and Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Olshanski","sequence":"additional","affiliation":[{"name":"Growth and Development Laboratory, Children's Hospital of Pittsburgh and Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M","family":"Ho","sequence":"additional","affiliation":[{"name":"Growth and Development Laboratory, Children's Hospital of Pittsburgh and Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Gearhart","sequence":"additional","affiliation":[{"name":"Growth and Development Laboratory, Children's Hospital of Pittsburgh and Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M","family":"Cooper","sequence":"additional","affiliation":[{"name":"Growth and Development Laboratory, Children's Hospital of Pittsburgh and Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Huard","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Biochemistry and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"},{"name":"Growth and Development Laboratory, Children's Hospital of Pittsburgh and Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024013019260434600_bib1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0925-4773(01)00601-3","article-title":"Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188","volume":"111","author":"Maes","year":"2002","journal-title":"Mech Dev"},{"key":"2024013019260434600_bib2","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1172\/JCI200419383","article-title":"Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival","volume":"113","author":"Maes","year":"2004","journal-title":"J Clin Invest"},{"key":"2024013019260434600_bib3","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/9467","article-title":"VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation","volume":"5","author":"Gerber","year":"1999","journal-title":"Nat Med"},{"key":"2024013019260434600_bib4","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1242\/dev.129.8.1893","article-title":"Skeletal defects in VEGF(120\/120) mice reveal multiple roles for VEGF in skeletogenesis","volume":"129","author":"Zelzer","year":"2002","journal-title":"Development"},{"key":"2024013019260434600_bib5","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1210\/endo.138.7.5275","article-title":"Anabolic effects of 1,25-dihydroxyvitamin D3 on osteoblasts are enhanced by vascular endothelial growth factor produced by osteoblasts and by growth factors produced by endothelial cells","volume":"138","author":"Wang","year":"1997","journal-title":"Endocrinology"},{"key":"2024013019260434600_bib6","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1172\/JCI15153","article-title":"Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4","volume":"110","author":"Peng","year":"2002","journal-title":"J Clin Invest"},{"key":"2024013019260434600_bib7","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1006\/mthe.2001.0291","article-title":"Exogenously regulated stem cell-mediated gene therapy for bone regeneration","volume":"3","author":"Moutsatsos","year":"2001","journal-title":"Mol Ther"},{"key":"2024013019260434600_bib8","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S8756-3282(97)00248-2","article-title":"Antiangiogenic agent (TNP-470) inhibition of ectopic bone formation induced by bone morphogenetic protein-2","volume":"22","author":"Mori","year":"1998","journal-title":"Bone"},{"key":"2024013019260434600_bib9","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1210\/endo.143.4.8719","article-title":"Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A.","volume":"143","author":"Deckers","year":"2002","journal-title":"Endocrinology"},{"key":"2024013019260434600_bib10","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1083\/jcb.151.4.879","article-title":"Matrix metalloproteinase 9 and vascular endothelial growth factor are essential for osteoclast recruitment into developing long bones","volume":"151","author":"Engsig","year":"2000","journal-title":"J Cell Biol"},{"key":"2024013019260434600_bib11","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0092-8674(00)81169-1","article-title":"MMP-9\/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes","volume":"93","author":"Vu","year":"1998","journal-title":"Cell"},{"key":"2024013019260434600_bib12","doi-asserted-by":"crossref","first-page":"4123","DOI":"10.1242\/dev.00559","article-title":"Altered fracture repair in the absence of MMP9","volume":"130","author":"Colnot","year":"2003","journal-title":"Development"},{"key":"2024013019260434600_bib13","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1083\/jcb.150.5.1085","article-title":"Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing","volume":"150","author":"Lee","year":"2000","journal-title":"J Cell Biol"},{"key":"2024013019260434600_bib14","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1084\/jem.170.2.399","article-title":"A human endothelial cell-restricted, externally disposed plasmalemmal protein enriched in intercellular junctions","volume":"170","author":"Muller","year":"1989","journal-title":"J Exp Med"},{"key":"2024013019260434600_bib15","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1359\/jbmr.2002.17.6.998","article-title":"Dissociation of angiogenesis and osteoclastogenesis during endochondral bone formation in neonatal mice","volume":"17","author":"Deckers","year":"2002","journal-title":"J Bone Miner Res"},{"key":"2024013019260434600_bib16","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1083\/jcb.119.2.475","article-title":"Isolation and characterization of an inhibitor of neovascularization from scapular chondrocytes","volume":"119","author":"Moses","year":"1992","journal-title":"J Cell Biol"},{"key":"2024013019260434600_bib17","doi-asserted-by":"crossref","first-page":"32419","DOI":"10.1074\/jbc.272.51.32419","article-title":"Identification of chondromodulin I as a novel endothelial cell growth inhibitor. Purification and its localization in the avascular zone of epiphyseal cartilage","volume":"272","author":"Hiraki","year":"1997","journal-title":"J Biol Chem"},{"key":"2024013019260434600_bib18","first-page":"39","article-title":"Spatiotemporal pattern of the mouse chondromodulin-I gene expression and its regulatory role in vascular invasion into cartilage during endochondral bone formation","volume":"43","author":"Shukunami","year":"1999","journal-title":"Int J Dev Biol"},{"key":"2024013019260434600_bib19","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1097\/00003086-200009000-00033","article-title":"Is human fracture hematoma inherently angiogenic?","volume":"378","author":"Street","year":"2000","journal-title":"Clin Orthop"},{"key":"2024013019260434600_bib20","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1097\/00006534-200206000-00033","article-title":"Hypoxia and VEGF up-regulate BMP-2 mRNA and protein expression in microvascular endothelial cells: Implications for fracture healing","volume":"109","author":"Bouletreau","year":"2002","journal-title":"Plast Reconstr Surg"},{"key":"2024013019260434600_bib21","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/S8756-3282(01)00690-1","article-title":"Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts","volume":"30","author":"Mayr-Wohlfart","year":"2002","journal-title":"Bone"},{"key":"2024013019260434600_bib22","doi-asserted-by":"crossref","first-page":"9656","DOI":"10.1073\/pnas.152324099","article-title":"Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover","volume":"99","author":"Street","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024013019260434600_bib23","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1002\/jgm.392","article-title":"Adenoviral VEGF-A gene transfer induces angiogenesis and promotes bone formation in healing osseous tissues","volume":"5","author":"Tarkka","year":"2003","journal-title":"J Gene Med"},{"key":"2024013019260434600_bib24","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0736-0266(02)00159-6","article-title":"Effects of locally applied vascular endothelial growth factor (VEGF) and VEGF-inhibitor to the rabbit tibia during distraction osteogenesis","volume":"21","author":"Eckardt","year":"2003","journal-title":"J Orthop Res"},{"key":"2024013019260434600_bib25","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1096\/fj.02-0514fje","article-title":"Adenovirus-mediated VEGF-A gene transfer induces bone formation in vivo","volume":"17","author":"Hiltunen","year":"2003","journal-title":"FASEB J"},{"key":"2024013019260434600_bib26","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/00003086-199801000-00006","article-title":"Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair","volume":"346","author":"Wozney","year":"1998","journal-title":"Clin Orthop"},{"issue":"Suppl 1","key":"2024013019260434600_bib27","first-page":"S128","article-title":"Delivery systems for BMPs: Factors contributing to protein retention at an application site","volume":"83","author":"Uludag","year":"2001","journal-title":"J Bone Joint Surg Am"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2FJBMR.050708","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/20\/11\/2017\/56475107\/5650201115.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/20\/11\/2017\/56475107\/5650201115.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T15:09:55Z","timestamp":1710342595000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/20\/11\/2017-2027\/7592827"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,11,1]]},"references-count":27,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[2005,11,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.050708","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2005,11,1]]},"published":{"date-parts":[[2005,11,1]]}}}