title: Teriparatide attenuates scarring around murine cranial bone allograft via modulation of angiogenesis.
abstract: Nearly all bone fractures in humans can deteriorate into a non-union fracture, often due to formation of fibrotic tissue. Cranial allogeneic bone grafts present a striking example: although seemingly attractive for craniofacial reconstructions, they often fail due to fibrosis at the host-graft junction, which physically prevents the desired bridging of bone between the host and graft and revitalization of the latter. In the present study we show that intermittent treatment with recombinant parathyroid hormone-analogue (teriparatide) modulates neovascularization feeding in the graft surroundings, consequently reducing fibrosis and scar tissue formation and facilitates osteogenesis. Longitudinal inspection of the vascular tree feeding the allograft has revealed that teriparatide induces formation of small-diameter vessels in the 1st week after surgery; by the 2nd week, abundant formation of small-diameter blood vessels was detected in untreated control animals, but far less in teriparatide-treated mice, although in total, more blood capillaries were detected in the animals that were given teriparatide. By that time point we observed expression of the profibrogenic mediator TGF-β in untreated animals, but negligible expression in the teriparatide-treated mice. To evaluate the formation of scar tissue, we utilized a magnetization transfer contrast MRI protocol to differentiate osteoid tissue from scar tissue, based on the characterization of collagen fibers. Using this method we found that significantly more bone matrix was formed in animals given teriparatide than in control animals. Altogether, our findings show how teriparatide diminishes scarring, ultimately leading to superior bone graft integration.
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem 91120, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Cohn Yakubovich
authors.affiliation: School of Chemistry, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Uzi
authors.initials: U
authors.lastname: Eliav
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem 91120, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Yalon
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem 91120, Israel.
authors.forename: Yeshai
authors.initials: Y
authors.lastname: Schary
authors.affiliation: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Sheyn
authors.affiliation: Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Galen
authors.initials: G
authors.lastname: Cook-Wiens
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Shuting
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem 91904, Israel; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Shaya
authors.initials: S
authors.lastname: Lev
authors.affiliation: Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University, Jerusalem 91904, Israel; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem 91904, Israel.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Binshtok
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem 91120, Israel; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Gadi
authors.initials: G
authors.lastname: Pelled
authors.affiliation: School of Chemistry, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Navon
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem 91120, Israel; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Gazit
authors.affiliation: Skeletal Biotech Laboratory, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem 91120, Israel; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: zulma.gazit@csmc.edu.
authors.forename: Zulma
authors.initials: Z
authors.lastname: Gazit
mesh_terms: D064591:Allografts / Q000187:drug effects*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development; D016025:Bone Transplantation / Q000009:adverse effects*; D002113:Calcification, Physiologic / Q000187:drug effects; D002921:Cicatrix / Q000188:drug therapy* / Q000209:etiology*; D005260:Female; D005355:Fibrosis; D008279:Magnetic Resonance Imaging; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012886:Skull / Q000473:pathology*; D019379:Teriparatide / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D019379:Teriparatide
keywords: Bioengineering; Bone anabolics; Bone injury; Fracture healing; Magnetic resonance imaging; Parathyroid hormone