Isoprenoid geranylgeraniol: the influence on cell characteristics of endothelial progenitor cells after bisphosphonate therapy in vitro

Abstract

Geranylgeraniol (GGOH) has been reported as a potential treatment option for bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ). The aim of this study was to analyze the effects of GGOH on endothelial progenitor cells (EPC) after bisphosphonate treatment in vitro. EPC were incubated with different nitrogen (N-BPs: ibandronate, pamidronate, zoledronate) and a non-nitrogen-containing bisphosphonates (NN-BP: clodronate) with and without GGOH. Cell viability was measured by MTT and PrestoBlue assay. Migration ability was analyzed with a Boyden and Scratch assay. Apoptosis rates were determined by colony-forming, Tunel and ToxiLight assays. Negative effects of N-BPs on EPC were shown in all tests without GGOH. The substitution of GGOH demonstrated significantly increased cell viability (MTT: p each N-BP ≤0.004; PrestoBlue: p each N-BP <0.001) and migration ability (Boyden: p each N-BP <0.001; Scratch: p each N-BP <0.001). Concerning the apoptosis rates, increased EPC colony densities (p each N-BP ≤0.009), decreased numbers of apoptotic cells in the Tunel assay (p each N-BP <0.001), and a decreased adenylate kinase release in the ToxiLight assay (p each N-BP ≤0.03) were observed. For the clodronate-treated cells, no significant differences could be detected with or without GGOH in any assay (p each N-BP/NN-BP >0.05). GGOH cell treatment reversed the negative effects of bisphosphonates on EPC. These findings support the hypothesis that systemic or local GGOH treatment might lead to new therapeutic strategies for BP-ONJ.