title: Bisphosphonates inhibit cell functions of HUVECs, fibroblasts and osteogenic cells via inhibition of protein geranylgeranylation.
abstract: OBJECTIVE
  Bisphosphonate-associated osteonecrosis of the jaw is a severe side effect in patients receiving nitrogen-containing bisphosphonates (N-BPs). One characteristic is its high recurrence rate; therefore, basic research for new therapeutic options is necessary. N-BPs inhibit the farnesylpyrophosphate synthase in the mevalonate pathway causing a depletion of the cellular geranylgeranyl pool, resulting in a constriction of essential functions of different cell lines. Geranylgeraniol (GGOH) has been proven to antagonise the negative biological in vitro effects of bisphosphonates.
  
  
  METHODS
  This study analyses the influence of the isoprenoids eugenol, farnesol, R-limonene, menthol and squalene on different functions of zoledronate-treated human umbilicord vein endothelial cells (HUVEC), fibroblasts and osteogenic cells. In addition to the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl 2H-tetrazolium bromide (MTT) vitality test, the migration capacity was analysed by scratch wound assay and the morphological architecture of the treated cells by phallacidin staining.
  
  
  RESULTS
  In contrast to GGOH, none of the other tested isoprenoids were able to prevent cells from having negative zoledronate effects.
  
  
  CONCLUSIONS
  Despite structural analogy to GGOH, the investigated isoprenoids are not able to prevent the N-BP effect. The negative impact of zoledronate on fibroblasts, HUVEC and osteogenic cells is due to inhibition of protein geranylgeranylation since the substitution of squalene and farnesyl did not have any effect on viability and wound healing capacity whereas GGOH did reduce the negative impact.
  
  
  CONCLUSIONS
  These data suggest the importance and exclusiveness of the mevalonate pathway intermediate GGOH as a potential therapeutic approach to bisphosphonate-associated osteonecrosis of the jaws.
authors.affiliation: Oral- and Maxillofacial Surgery, University Medical Center, Johannes Gutenberg University, Augustusplatz 2, 55131, Mainz, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hagelauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Ziebart
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Pabst
authors.forename: Christian
authors.initials: C
authors.lastname: Walter
mesh_terms: D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000517:prevention & control; D050071:Bone Density Conservation Agents / Q000633:toxicity*; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053138:Cyclohexenes / Q000494:pharmacology; D004164:Diphosphonates / Q000633:toxicity*; D004224:Diterpenes / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects*; D005054:Eugenol / Q000494:pharmacology; D005204:Farnesol / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D000077222:Limonene; D008610:Menthol / Q000494:pharmacology; D010012:Osteogenesis / Q000187:drug effects; D017368:Protein Prenylation; D012008:Recurrence; D013185:Squalene / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D053138:Cyclohexenes; D004164:Diphosphonates; D004224:Diterpenes; D007093:Imidazoles; D013729:Terpenes; D008610:Menthol; D005054:Eugenol; D005204:Farnesol; D000077211:Zoledronic Acid; D013185:Squalene; D000077222:Limonene; C017338:geranylgeraniol