Experimental Repositioning of Geranylgeranylacetone to Enhance Bone Remodeling

Abstract

: Drug repositioning (DR) is a strategy to explore new medicinal effects from existing approved drugs whose safety and pharmacokinetics have already been established. We focused on geranylgeranylacetone (GGA), which is known as a heat shock proteins (HSPs) inducing agent. GGA is mainly used as a gastric mucosal protective agent; however, its effects on bone tissues have not been studied. Therefore, we hypothesized that “GGA induces HSPs in osteoblasts thereby promotes cell differentiation”, and administered GGA to MC3T3E-1 cells to examine cell responses. Methods: MC3T3E-1 were cultured in osteogenic medium. After the cultures were established, test cultures were exposed to GGA (GGA group). Cell proliferation, collage synthesis and ALP activity were measured on days 7 and 14 of culture. Alizarin Red S staining was performed on days 21 of culture. Results: On days 14 of culture, cell proliferation and collage synthesis were signifi cantly higher in the GGA group than in the control group (P<0.05). On days 7 and 14 of culture, ALP activity was signifi cantly higher in the GGA group than in the Control group (P<0.05). On days 28 of culture, the Alizarin Red S stained areas were significantly higher in the GGA group than in the control group (P<0.05). Conclusion: GGA promoted the differentia tion of MC3T3E-1 in an in vitro cell culture model. We hypothesized that GGA upregulates HSPs and promotes osteoblast differentiation and tested our hypothesis using a series of in vitro experiments. We investigated the responses and phenotypic changes occurring in MC3T3E-1 mouse osteoblast-like cells exposed to GGA. A 10 -3 M GGA concentration was applied to all cell cultures as preliminary assays demonstrated that it was the minimum concentration necessary to produce different calcification levels (unpub lished data).