title: The influence of geranylgeraniol on microvessel sprouting after bisphosphonate substitution in an in vitro 3D-angiogenesis assay.
abstract: OBJECTIVE
  Recent studies focused on angiogenesis in the pathophysiology of bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) and identified geranylgeraniol (GGOH) as a feasible option for BP-ONJ therapy. This study investigated the influence of GGOH on microvessel sprouting after BP-incubation in vitro.
  
  
  METHODS
  Ten experimental set-ups were randomly designed in an in vitro 3D-angiogenesis assay. Two groups included HUVEC cell spheroids with and without (±) GGOH substitution as controls and eight groups pairwise contained either clodronate or the nitrogen-containing bisphosphonates (N-BP) ibandronate, pamidronate, and zoledronate ± GGOH. The size of the cell spheroids including the outbranching sprouts (SpS) as well as the density (SpD) and length of the sprouts (SpL) were analyzed by a grid system after 0, 24, 48, and 72 h.
  
  
  RESULTS
  For controls and NN-BP clodronate, no significant differences at any tested parameter and any point of measurement could be detected within the experimental set-ups ± GGOH (p each ≥0.05). For N-BP ibandronate, the experimental set-ups +GGOH showed a significantly increased SpS, SpD, and SpL after 48 and 72 h (p each ≤0.002) compared to the experimental set-ups -GGOH. For N-BPs pamidronate and zoledronate, the experimental set-ups + GGOH demonstrated a significantly increased SpS, SpD, and SpL after 24, 48, and 72 h (p each ≤0.001) compared to the experimental set-ups -GGOH.
  
  
  CONCLUSIONS
  The strong negative influence of N-BPs on microvessel sprouting could be significantly reversed by GGOH.
  
  
  CONCLUSIONS
  Since supportive therapeutic options for BP-ONJ are lacking, GGOH might be a promising substitute for BP-ONJ prevention and therapy.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Federal Armed Forces Hospital, Rübenacherstr, 170, 56072, Koblenz, Germany. andipabst@me.com.|Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany. andipabst@me.com.
authors.forename: A M
authors.initials: AM
authors.lastname: Pabst
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Krüger
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Sagheb
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Clinic, Georg-Voigt-Straße 3, 35039, Marburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Ziebart
authors.affiliation: Department of Orthodontics, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Jacobs
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Blatt
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Goetze
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131, Mainz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Walter
mesh_terms: D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000188:drug therapy*; D050071:Bone Density Conservation Agents / Q000009:adverse effects* / Q000494:pharmacology*; D004164:Diphosphonates / Q000009:adverse effects* / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D055806:Microvessels / Q000187:drug effects*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004224:Diterpenes; C017338:geranylgeraniol
keywords: Angiogenesis; BP-ONJ; Bisphosphonate; Geranylgeraniol; Isoprenoid; Osteonecrosis