SRT2183 and SRT1720, but not resveratrol, inhibit osteoclast formation and resorption in the presence or absence of Sirt1
Osteoclastic bone resorption markedly increases with aging, leading to osteoporosis characterized by weak and fragile bones. Mice exhibit greater bone resorption and poor bone mass when Sirt1 is removed from their osteoclasts. Here we investigated the ex vivo impacts of putative Sirt1 activators, resveratrol (RSV), SRT2183 and SRT1720, on osteoclast formation and activity in primary mouse bone marrow cells (BMCs) derived from wild type (WT) and osteoclast specific Sirt1 knockout (OC-Sirt1KO) mice and in the RAW264.7 mouse macrophage cell line. We found that SRT2183 and SRT1720 inhibit formation of osteoclasts and actin rings in both BMCs and RAW264.7 cells, whereas RSV does not. We also observed that the OC-Sirt1KO mice exhibited less bone mineral density, and the BMCs harvested from these mice yielded more osteoclasts than BMCs harvested from littermate controls. Interestingly, both SRT2183 and SRT1720 reduced osteoclast and actin ring formation in BMCs from OC-Sirt1KO mice. SRT2183 and SRT1720 also significantly disrupted actin belts of mature osteoclasts from WT mice BMCs, within 3 and 6 hours of administration, respectively. Furthermore, these compounds inhibited resorption activity of mature osteoclasts, while RSV did not. Our findings suggest SRT2183 and SRT1720 impede bone resorption by disrupting actin belts of mature osteoclasts, inhibit actin ring formation in osteoclast precursors, and inhibit osteoclastogenesis even in the absence of Sirt1. Thus, further understanding the mechanism of action of these compounds may pave the way for potential new therapies in alleviating osteoporosis associated bone loss.