OPG, which is produced and secreted from osteoblasts, binds to RANKL as a decoy receptor and inhibits the binding of RANKL to RANK, an essential step of osteoclastogenesis

Resveratrol is a natural polyphenol found in red grape skins, berries and red wine. Accumulating evidence suggests that resveratrol has various beneficial effects on the human body. In the present study, we investigated the effects of prostaglandin E2 (PGE2) on osteoprotegerin (OPG) synthesis and the effects of resveratrol on OPG synthesis in osteoblastlike MC3T3-E1 cells. PGE2 significantly stimulated both the release of OPG and the mRNA expression levels of OPG, as shown by OPG assay and real-time RT-PCR, respectively. Resveratrol markedly suppressed the release and the mRNA levels of OPG induced by PGE2. On the contrary, SRT1720, an activator of sirtuin 1 (SIRT1), hardly affected the PGE2-induced release of OPG. PD98059 [a specific inhibitor of the upstream kinase that activates p44/p42 mitogen-activated protein (MAP) kinase], SB203580 (a specific inhibitor of p38 MAP kinase) and SP600125 [a specific inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)], reduced the PGE2-induced release of OPG. Resveratrol attenuated the PGE2-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK. However, SRT1720 failed to affect the phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK induced by PGE2. These results strongly suggest that resveratrol reduces PGE2-stimulated OPG synthesis through the inhibition of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK in osteoblasts, and that these suppressive effects are independent of the activation of SIRT1.