Geranylgeraniol - a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw

Abstract

Bisphosphonate associated osteonecrosis of the jaw (BP-ONJ) is one of the main side effects of bisphosphonate therapy (BPT). To date, there is no effective therapy of the BP-ONJ. Nitrogen-containing bisphosphonates (N-BPs) are particularly able to inhibit pyrophosphate synthase (FPPS) in the mevalonate pathway (MVP). Consequent of decreased synthesis of the metabolite Geranylgeraniol (GGOH) is believed to largely account for the development of BP-ONJ. Negative effect of N-BPs could be shown, resulting in decreased viability and migration capacity of different cell types of hard and soft tissues such as osteoblasts, fibroblast und endothelial cells. Aim of our in vitro study was to demonstrate that the mevalonate pathway metabolite GGOH could reverse the negative biological effect of N-BPs. Biological effect of GGOH on bisphosphonate-treated human umbilicord vein endothelial cells (HUVEC), fibroblast and osteogenic cells was analyzed by a viability test and measuring the migration capacity in a scratch wound assay as well as a migration assay using Boyden chambers. The morphological cell architecture of the treated cells was analyzed by phallacidin staining. GGOH cell-treatment can rescue the negative effect of bisphosphonates. These results underline the hypothesis that systemic or local treatment with GGOH could lead to new therapeutic strategies for BP-ONJ.