title: Low zoledronate concentrations stimulate human keratinocyte proliferation.
abstract: OBJECTIVE
  To evaluate, in an in vitro wound healing model, the effect of zoledronate on keratinocyte cellular behavior.
  
  
  METHODS
  Human spontaneously immortalized keratinocytes (HaCaT) were treated with low zoledronate concentrations (10 nmol/l to 10 µmol/l) and its effect on cell proliferation was evaluated by means of a fluorescent assay (Tox-8), along with the analysis of cytokeratin 5 and filaggrin gene expression. Moreover, zoledronate effects on cell migration were evaluated by in vitro wound healing, and matrix metalloproteinase (MMP) activity was investigated by gelatin zymography.
  
  
  RESULTS
  At the tested concentrations, zoledronate stimulated keratinocyte proliferation, upregulating cytokeratin 5 while downregulating filaggrin expression and wound healing ability, without any significant effect on MMP-9 activity. The lack of zoledronate effects on MMP-9 activity indicates that, in our experimental model, wound closure is mainly due to an increase in cell proliferation rather than an increase in cell migration. Moreover, the observed increase in cell proliferation could be ascribed to a zoledronate-mediated reduction of farnesyl pyrophosphate endogenous levels.
  
  
  CONCLUSIONS
  These results could foster new clinical applications for this 'old' drug in the field of epithelial regeneration.
authors: Dental Clinic, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy.
authors: Mario
authors: M
authors: Migliario
authors: Manuela
authors: M
authors: Rizzi
authors: Vincenzo
authors: V
authors: Rocchetti
authors: Pamela
authors: P
authors: Pittarella
authors: Filippo
authors: F
authors: Renò
mesh_terms: D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D000091344:Filaggrin Proteins; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007381:Intermediate Filament Proteins / Q000235:genetics; D053555:Keratin-5 / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007093:Imidazoles; D007381:Intermediate Filament Proteins; D053555:Keratin-5; D000077211:Zoledronic Acid; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9