Use of geranylgeraniol (GGOH) to rescue bone regeneration impaired by bisphosphonate-- an in vivo study
Date Issued
2014
Date
2014
Author(s)
Wang, Huey-Jen
Abstract
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one of the main side effects of bisphosphonate therapy (BPT). To date, there is no effective therapy of the BRONJ. Nitrogen-containing bisphosphonates (N-BPs) target to the inhibition of pyrophosphate synthase (FPPS) in the mevalonate pathway. Consequently, decreased synthesis of the downstream metabolites, geranylgeraniol (GGOH) and farnesol (FOH), is believed to largely account for the development of BRONJ. Previous in vitro studies have shown the negative effects of N-BPs on decreased viability and migration capacity of different cell types. The aim of our study was to demonstrate that the application of downstream metabolites may reverse the negative biological effects of N-BPs.
Amputation-regeneration model of zebrafish caudal fin was employed to analyze the effects of drug administration. Alendronate (N-BP), farnesol, and geranylgeraniol at 7.5×10-5M were used to treat the fish by incubation. The regenerated bones in the fin were documented by calcein staining. The dynamic appearance of ostelclasts during the process was observed by TRAP staining.
The bone regeneration impaired by alendronate was reversed to normal in the presence of GGOH and FOH. In addition, the morphological restoration was delineated by TRAP staining to reveal the distribution of osteoclasts. The results showed that the number and distribution of osteoclasts were restored to normal likewise. Hence, systemic application of GGOH and FOH may reduce the side effects of bisphosphonate therapy.
In this study, we demonstrate that the impairing effects of alendronate on bone regeneration and osteoclast activities may be reversed by application of GGOH and FOH. Our study in zebrafish provides a vivid animal model to investigate the BRONJ in vivo. And the results may further extend to the clinical applications in treating BRONJ.
Subjects
雙磷酸鹽
顎骨壞死
挽救
香葉基香葉醇
斑馬魚
Type
thesis
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