Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone-derived cells.
J Biol Chem. 2011 Jan 14. Epub 2011 Jan 14. PMID: 21239502
Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, 80336 Munich, Germany;
Resveratrol is a polyphenolic phyto-estrogen that has been shown to exhibit potent anti-oxidant, anti-inflammatory and anti-catabolic properties. Increased osteoclastic and decreased osteoblastic activity result in bone resorption and loss of bone mass. These changes have been implicated in pathological processes in rheumatoid arthritis (RA) and osteoporosis. Receptor activator of NF-kappaB ligand (RANKL), a member of the TNF superfamily, is a major mediator of bone loss. In this study we investigated the effects of resveratrol on RANKL during bone morphogenesis in high-density bone cultures in vitro. Untreated bone-derived cell cultures produced well-organized bone-like structures with a bone specific matrix. Treatment with RANKL induced formation of TRAP positive multinucleated cells that exhibited morphological features of osteoclasts. RANKL induced NF-kappaB activation, whereas pre-treatment with resveratrol completely inhibited this activation, suppressed the activation of IkappaBα kinase, IkappaBα phosphorylation and degradation. RANKL up-regulated p300 (a histone acetyltransferase) expression, which, in turn, promoted acetylation of NF-kappaB. Resveratrol inhibited RANKL-induced acetylation and nuclear translocation of NF-kappaB in a time and concentration dependent manner. In addition, activation of Sirt-1 (a histone deacetylase) by resveratrol induced Sirt-1-p300 association in bone-derived and pre-osteoblastic cells, leading to deacetylation of RANKL-induced NF-kappaB, inhibition of NF-kappaB transcriptional activation and osteoclastogenesis. Co-treatment with resveratrol activated the bone transcription factor Cbfa-1, Sirt-1 and induced the formation of Sirt-1/Cbfa-1-complexes. Overall, these results demonstrate that resveratrol-activated Sirt-1 plays pivotal roles in regulating the balance between osteoclastic versus osteoblastic activity result in boneformation in vitro thereby highlighting its therapeutic potential for treating osteoporosis and RA-related bone loss.