Geranylgeraniol Overcomes the Deleterious Effect of Nitrogen Containing Bisphosphonates on Osteoclasts by Promoting G-protein Expression

The nitrogen containing bisphosphonates (NBP), pamidronate, is considered to be responsible for Medication Related Osteonecrosis of the Jaw, MRONJ. By inhibiting the prenylation of G-proteins necessary for osteoclast survival, the NBP blocks the synthesis of geranylgeraniol(GGOH) in the mevalonic acid pathway.The goal of the study is to assess the effect of pamidronate on global gene expression and determine whether administration of GGOH can restore gene expression. RAW osteoclast-like cells were maintained in monolayer culture and treated with RANKL in the presence and absence of NBP.Pamidronate-treated cells were also treated with GGOH to restore normal function. RNA was extracted from pelleted RANKL-treated cells, sequenced and pathway analyzed. Pamidronate downregulated genes associated with immune function, oxidative metabolism and osteoclast differentiation and function.Surprisingly, Rho j, a small GTPase was down-regulated 238 fold while RGS18 protein, a regulator of G-protein signaling, was repressed 126 fold. Substantial changes in expression of more than twenty other G-proteins were observed.When cells were treated with GGOH, many of the inhibitory effects of the NBP were abrogated and G-protein expression was preserved. The observation that GGOH overcomes the deleterious effect of NBP on osteoclasts by promoting G-protein expression, suggests a novel therapeutic approach to preventing or treating MRONJ.