title: Stimulation of angiogenesis by cilostazol accelerates fracture healing in mice.
abstract: Cilostazol, a selective phosphodiesterase-3 inhibitor, is known to control cyclic adenosine monophosphate (c-AMP) and to stimulate angiogenesis through upregulation of pro-angiogenic factors. There is no information, however, whether cilostazol affects fracture healing. We, therefore, studied the effect of cilostazol on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine femur fracture stabilized with an intramedullary screw. Radiological, biomechanical, histomorphometric, histochemical, and protein biochemical analyses were performed at 2 and 5 weeks after fracture. Twenty-five mice received 30 mg/kg body weight cilostazol p.o. daily. Controls (n=24) received equivalent amounts of vehicle. In cilostazol-treated animals radiological analysis at 2 weeks showed an improved healing with an accelerated osseous bridging compared to controls. This was associated with a significantly higher amount of bony tissue and a smaller amount of cartilage tissue within the callus. Western blot analysis showed a higher expression of cysteine-rich protein 61 (CYR61), bone morphogenetic protein (BMP)-4, and receptor activator of NF-kappaB ligand (RANKL). At 5 weeks, improved fracture healing after cilostazol treatment was indicated by biomechanical analyses, demonstrating a significant higher bending stiffness compared to controls. Thus, cilostazol improves fracture healing by accelerating both bone formation and callus remodeling.
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Herath
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lion
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Klein
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Stenger
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Holstein
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Mörsdorf
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Mika F R
authors.initials: MF
authors.lastname: Rollmann
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Pohlemann
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Saarland University, Homburg, Saarland, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Histing
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D001863:Bone Screws; D002146:Bony Callus / Q000187:drug effects; D000077407:Cilostazol; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism; D005264:Femoral Fractures / Q000188:drug therapy*; D005269:Femur / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017102:Fracture Healing / Q000187:drug effects*; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic; D058987:Phosphodiesterase 3 Inhibitors / Q000627:therapeutic use; D053245:RANK Ligand / Q000378:metabolism; D013777:Tetrazoles / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D058987:Phosphodiesterase 3 Inhibitors; D053245:RANK Ligand; D013777:Tetrazoles; C505689:Tnfsf11 protein, mouse; D014665:Vasodilator Agents; D000077407:Cilostazol
keywords: BMP-4; CYR61; RANKL; cilostazol; fracture healing