The Polyphenol Rsesveratrol Promotes Skeletal Growth in Mice Through a SirT1-BMP2 Longevity Axis.
Zhao M., Ko S-Y., Ross Garrett I., Mundy GR., Gutierrez GE., Edwards JR.
BACKGROUND AND PURPOSE: The polyphenol Resveratrol (RSV) exists in high quantities in certain foods (e.g. grapes, nuts) . However, the capacity of RSV to confer physiological health benefits and a biological mechanism through which this might occur remains unclear. EXPERIMENTAL APPROACH: This study employs aged, RSV-treated (300mg/kg/day) and genetically modified (eNOS-/- ) female mice assessed using histomorphometric and microCT analysis. Alongside in vivo analysis molecular siRNA knockdown and pharmacological manipulation of eNOS, BMP2 and SirT1 and functional cellular assays in an osteoblast cell line panel, explored the mechanism through which RSV might impact overall bone volume. KEY RESULTS: We show that RSV promotes osteoblast activity and bone growth in vivo. RSV dose-dependently and simultaneously increased alkaline phosphatase (ALP) and eNOS levels. Similarly, NO-donor treatment increased ALP, Runx2, BMP2 and stimulated bone formation, whilst eNOS-deficient mice displayed a bone loss phenotype. Moreover, RSV-induced increase in ALP and BMP2 expression was blocked in eNOS-/- osteoblasts and by the BMP-inhibitor noggin. The longevity-linked SirT1 enzyme is positively regulated by RSV and SirT1 deletion reduces eNOS, BMP2 and ALP. Like eNOS deletion, loss of SirT1 blocked RSV-induced osteoblast activity however, SirT1 levels remained unchanged in eNOS-/- mice, indicating RSV activation of SirT1 stimulates BMP2 release via eNOS. This signaling axis is supported by decreased SirT1, eNOS and BMP2 confirmed in old vs young bone. CONCLUSION AND IMPLICATIONS: These findings suggest a new mechanism of action in bone remodeling and the ageing skeleton, where RSV positively impacts bone homeostasis via SirT1 activation of BMP2.