title: Endostatin inhibits Callus remodeling during fracture healing in mice.
abstract: Information on the impact of endogenous anti-angiogenic factors on bone repair is limited. The hypothesis of the present study was endostatin, an endogenous inhibitor of angiogenesis, disturbs fracture healing. We evaluated this hypothesis in a closed femoral fracture model studying two groups of mice, one that was treated by a daily injection of 10 µg recombinant endostatin subcutaneously (n = 38) and a second one that received the vehicle for control (n = 37). Histomorphometric analysis showed a significantly increased callus formation in endostatin-treated animals at 2 and 5 weeks post-fracture. This was associated with a significantly higher callus tissue fraction of cartilage and fibrous tissue at 2 weeks and a significantly higher fraction of bone at 5 weeks post-fracture. Biomechanical testing revealed a significantly higher torsional stiffness in the endostatin group at 2 weeks. For both groups, we could demonstrate the expression of the endostatin receptor unit integrin alpha5 in endothelial cells, osteoblasts, osteoclasts, and chondrocytes at 2 weeks. Immunohistochemical fluorescence staining of CD31 showed a lower number of blood vessels in endostatin-treated animals compared to controls. The results of the present study indicate endostatin promotes soft callus formation but inhibits callus remodeling during fracture healing most probably by an inhibition of angiogenesis.
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University of Saarland, Kirrberger Strasse, 66421, Homburg/Saar, Germany. joerg.holstein@uks.eu
authors.forename: Joerg H
authors.initials: JH
authors.lastname: Holstein
authors.forename: Bianca
authors.initials: B
authors.lastname: Karabin-Kehl
authors.forename: Claudia
authors.initials: C
authors.lastname: Scheuer
authors.forename: Patric
authors.initials: P
authors.lastname: Garcia
authors.forename: Tina
authors.initials: T
authors.lastname: Histing
authors.forename: Christoph
authors.initials: C
authors.lastname: Meier
authors.forename: Emanuel
authors.initials: E
authors.lastname: Benninger
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Tim
authors.initials: T
authors.lastname: Pohlemann
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects / Q000502:physiology; D002146:Bony Callus / Q000502:physiology*; D019902:Chondrocytes / Q000502:physiology; D043169:Endostatins / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D017102:Fracture Healing / Q000187:drug effects / Q000502:physiology*; D039482:Integrin alpha5 / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology; D011859:Radiography; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D039482:Integrin alpha5; D011994:Recombinant Proteins
keywords: angiogenesis; endostatin; fracture healing; integrin alpha5; mice