title: Formononetin promotes early fracture healing through stimulating angiogenesis by up-regulating VEGFR-2/Flk-1 in a rat fracture model.
abstract: Plant-derived phytoestrogens have bone protective effects, but the molecular mechanism behind these effects remains unclear. This study is aimed at fully characterizing the fracture healing process of formononetin, and investigating the mechanism underlying angiogenesis in calluses of a rat fracture model. Femoral fractures were produced in 2-month-old Sprague-Dawley rats. A 20 microg/kg or 200 microg/kg dose of formononetin was orally administrated once a day during the healing period of 21 days. The results showed that in the early stage of chondrogenesis (days 3), formononetin significantly increased the number of vessels, and expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2/flk-1) compared with control. However, the larger dose of formononetin had no significant difference on expression of VEGF and VEGFR-2/Flk-1 compared with that of the smaller dose of formononetin. After 7 days of administration, formononetin markedly induced differentiation of mesenchymal stem cells in the fracture site. After 14 days, gene expression of mesenchymal progenitors such as alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OPN) and collagen type I (Col I), indicating osteogenic differentiation, was markedly stimulated by formononetin compared with control. These results suggest that formononetin promotes early fracture healing through angiogenesis activation in the early stage of fracture repair, and osteogenesis acceleration in the later stages, and thus may be beneficial for fracture healing.
authors.affiliation: Oriental Medicine Research Center for Bone & Joint Disease, KyungHee University, 149, Sangil-dong, Gangdong-gu, Seoul, 134-727, Republic of Korea.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Huh
authors.forename: Na-Hyun
authors.initials: NH
authors.lastname: Kwon
authors.forename: Young-Hyun
authors.initials: YH
authors.lastname: Baek
authors.forename: Jae-Dong
authors.initials: JD
authors.lastname: Lee
authors.forename: Do-Young
authors.initials: DY
authors.lastname: Choi
authors.forename: Seiya
authors.initials: S
authors.lastname: Jingushi
authors.forename: Kang-il
authors.initials: KI
authors.lastname: Kim
authors.forename: Dong-Suk
authors.initials: DS
authors.lastname: Park
mesh_terms: D000818:Animals; D027885:Astragalus propinquus; D002146:Bony Callus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D020219:Chondrogenesis / Q000187:drug effects / Q000502:physiology; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005269:Femur / Q000098:blood supply / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D050723:Fractures, Bone / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007529:Isoflavones / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D048789:Phytoestrogens / Q000008:administration & dosage* / Q000737:chemistry; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage; D018517:Plant Roots; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D024042:Collagen Type I; D007529:Isoflavones; D048789:Phytoestrogens; D010936:Plant Extracts; D042461:Vascular Endothelial Growth Factor A; D015675:Osteocalcin; D053495:Osteopontin; C007768:formononetin; D040262:Receptors, Vascular Endothelial Growth Factor