Geranylgeraniol promotes osteoblast differentiation and inhibits osteoclastogenesis through MAPK and nuclear receptor signaling.

Bone is regulated in a coordinated manner through the catabolic action of osteoclasts and the anabolic function of osteoblasts. Geranylgeraniol (GGOH) is a diterpenoid alcohol found in plant oils and is an intermediate in the mevalonate pathway. GGOH suppressed receptor activator of NF-κB ligand (RANKL)-induced tartrate-resistant acid phosphatase-positive multinuclear osteoclast formation via downregulation of nuclear factor of activated T-cells cytoplasmic 1 expression. Among the RANKL-activated mitogen-activated protein kinases in bone marrow cells, phosphorylation of c-Jun amino-terminal kinase was significantly suppressed following GGOH treatment. In contrast, GGOH stimulates alkaline phosphatase (ALP) activity and mineralization in calvarial osteoblasts. GGOH increased the expression of osteoblast biomarkers such as collagen type 1 and ALP, and osteogenic genes, such as Msx2, Runx2, and Smad. Mitogen-activated protein kinase signaling pathway (c-Jun amino-terminal kinase, p38, extracellular signal-regulated kinase) and NF-κB were augmented by GGOH. GGOH-induced ALP expression was suppressed by a farnesoid X receptor (FXR) antagonist, whereas FXR agonist increased ALP activity in osteoblasts. In contrast, the suppressive effect of GGOH on RANKL-induced tartrate-resistant acid phosphatase activity in osteoclasts was attenuated by liver X receptor and FXR antagonists, and these agonists mimicked the effect of GGOH. GGOH restored bisphosphonate-suppressed osteoblast differentiation. GGOH also showed protective effects against lipopolysaccharide -induced bone resorption both in vitro and in vivo. Furthermore, GGOH treatment improved bone loss in ovariectomized mice. These results suggest that GGOH is a potent osteogenic and osteoprotective factor that promotes osteoblast differentiation and suppresses osteoclast differentiation, at least through nuclear receptor activation.