Low zoledronate concentrations stimulate human keratinocyte proliferation

AIM: To evaluate, in an in vitro wound healing model, the effect of zoledronate on keratinocyte cellular behavior. MATERIALS AND 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.