title: Protein isoprenylation regulates osteogenic differentiation of mesenchymal stem cells: effect of alendronate, and farnesyl and geranylgeranyl transferase inhibitors.
abstract: OBJECTIVE
  Protein isoprenylation is an important step in the intracellular signalling pathway conducting cell growth and differentiation. In bone, protein isoprenylation is required for osteoclast differentiation and activation. However, its role in osteoblast differentiation and function remains unknown. In this study, we assessed the role of protein isoprenylation in osteoblastogenesis in a model of mesenchymal stem cells (MSC) differentiation.
  
  
  METHODS
  We tested the effect of an inhibitor of farnesylation [farnesyl transferase inhibitor-277 (FTI-277)] and one of geranylgeranylation [geranylgeranyltransferase inhibitor-298 (GGTI-298)] on osteoblast differentiating MSC. In addition, we tested the effect of alendronate on protein isoprenylation in this model either alone or in combination with other inhibitors of isoprenylation.
  
  
  RESULTS
  Initially, we found that levels of unfarnesylated proteins (prelamin A and HDJ-2) increased after treatment with FTI-277 concomitantly affecting osteoblastogenesis and increasing nuclear morphological changes without affecting cell survival. Furthermore, inhibition of geranylgeranylation by GGTI-298 alone increased osteoblastogenesis. This effect was enhanced by the combination of GGTI-298 and alendronate in the osteogenic media.
  
  
  CONCLUSIONS
  Our data indicate that both farnesylation and geranylgeranylation play a role in osteoblastogenesis. In addition, a new mechanism of action for alendronate on protein isoprenylation in osteogenic differentiating MSC in vitro was found. In conclusion, protein isoprenylation is an important component of the osteoblast differentiation process that could constitute a new therapeutic target for osteoporosis in the future.
authors.affiliation: Ageing Bone Research Program, Sydney Medical School - Nepean Campus, The University of Sydney, Penrith, NSW, Australia. gustavo.duque@sydney.edu.au
authors.forename: G
authors.initials: G
authors.lastname: Duque
authors.forename: C
authors.initials: C
authors.lastname: Vidal
authors.forename: D
authors.initials: D
authors.lastname: Rivas
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000494:pharmacology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology; D017368:Protein Prenylation / Q000187:drug effects
chemical_list: D001549:Benzamides; D050071:Bone Density Conservation Agents; D004791:Enzyme Inhibitors; C096856:FTI 277; C102521:GGTI 298; D008715:Methionine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D019386:Alendronate