title: Low concentration amino-bisphosphonates stimulate human keratinocyte proliferation and in vitro wound healing.
abstract: Amino-bisphosphonates (N-BPs) are widely used to treat a great variety of clinical conditions involving altered calcium metabolism, as well as to prevent bone metastases. The use of N-BPs, however, display well-known side effects, including cellular toxicity, mainly at soft tissue and mucosal level, that arise from N-BPs ability to induce cell apoptosis when administered at clinically relevant concentrations. The aim of this study was to evaluate, in an in vitro wound healing model, the effect of N-BPs low concentration (10 nM-10 µM) stimulation on keratinocyte cellular behaviour. Human keratinocytes were treated with neridronate and zoledronate, two N-BPs with different chemical structure and clinical potency, but sharing a common pharmacological target: farnesyl pyrophosphate (FPP) synthase. Surprisingly, at the tested concentrations, both drugs stimulated keratinocytes proliferation, upregulating cytokeratin 5 while downregulating filaggrin expression, and wound healing ability, without any significant effect on matrix metalloproteinase (MMP)-9 activity. The lack of N-BPs effect on MMP-9 activity indicates that wound closure, in our experimental model, is mainly due to an increase in cell proliferation rather than to an increase in cell migration. Therefore, it can be hypothesised that the observed wound healing results could be ascribed to an N-BPs mediated reduction of FPP endogenous levels, thus suggesting new possible clinical applications for these compounds.
authors.affiliation: Human Anatomy Laboratory, Experimental and Clinical Medicine Department, University of Eastern Piedmont A. Avogadro, Via Solaroli, 17, 28100 Novara, Italy. filippo.reno@med.unipmn.it
authors.forename: Filippo
authors.initials: F
authors.lastname: Renò
authors.forename: Mario
authors.initials: M
authors.lastname: Migliario
authors.forename: Manuela
authors.initials: M
authors.lastname: Rizzi
authors.forename: Marco
authors.initials: M
authors.lastname: Invernizzi
authors.forename: Carlo
authors.initials: C
authors.lastname: Cisari
authors.forename: Mario
authors.initials: M
authors.lastname: Cannas
mesh_terms: D000328:Adult; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000091344:Filaggrin Proteins; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D014945:Wound Healing / Q000187:drug effects*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007093:Imidazoles; D000077211:Zoledronic Acid