Resveratrol reduces prostaglandin E1-stimulated osteoprotegerin synthesis in osteoblasts: Suppression of stress-activated protein kinase/c-Jun N-terminal kinase

Resveratrol, a natural polyphenol mainly existing in red grapes and berries, possesses beneficial effects on human being. We have previously reported that prostaglandin E-1 (PGE(1)) stimulates vascular endothelial growth factor synthesis via activation of p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) but not p44/p42 MAP kinase in osteoblast-like MC3T3-E-1 cells. In the present study, we investigated the PGE(1)-effect on osteoprotegerin (OPG) synthesis and the effect of resveratrol on the synthesis in MC3T3-E1 cells. PGE(1) induced the expression levels of OPG mRNA and stimulated the OPG release. Resveratrol significantly reduced the PGE(1)-induced OPG release and the mRNA expression. SRT1720, an activator of SIRT1, suppressed the release of OPG. The protein levels of SIRT1 were not up-regulated by resveratrol with or without PGE(1). Both SB203580 and SP600125, a specific p38 MAP kinase inhibitor and a specific SAPK/JNK inhibitor, respectively, but not PD98059, a specific MEK inhibitor, reduced the PGE(1)-stimulated OPG release. Resveratrol or SRT1720 failed to affect the phosphorylation of p38 MAP kinase. On the contrary, PGE(1)-induced phosphorylation of SAPK/JNK was significantly attenuated by both resveratrol and SRT1720. Our results strongly suggest that resveratrol inhibits PGE(1)-stimulated OPG synthesis via suppressing SAPK/JNK but not p38 MAP kinase in osteoblasts. (C) 2015 Elsevier Inc. All rights reserved.