Session: OR24-New Mechanisms in Bone Biology: From Cells to Genetics, & Mice to Men
Room 121 (Moscone Center)
We investigated whether the STAC SRTAW04 can restore bone mass and architecture in ovariectomized mice.
Nine week-old C57BL6/J female mice were subjected to bilateral ovariectomy or sham operation, and were left untreated for 6 weeks to allow for bone loss. Ovariectomized mice were treated daily with either SRTAW04 at 50 mg/kg, 100 mg/kg or a vehicle administered by gavage for 6 weeks. The fourth vertebrae, femurs and tibiae were removed for μCT, biomechanical testing, protein and mRNA analyses. To investigate SRTAW04 mechanism of action, in vitro studies in primary cultures in osteoblasts and osteoclasts were conducted.
Ovariectomy induced a 42%, 34% and 8% reduction in vertebral bone volume/total volume, trabecular number and thickness, respectively and increased trabecular bone pattern factor (TBPf), an index of trabecular architecture by 21%. SRTAW04 administered at 50 mg/kg completely restored these parameters (+70%, +49%, +13%, respectively), and decreased TBPf by 40%. Femoral stiffness was reduced by 22% after ovariectomy but was restored to control levels upon treatment. Protein analysis of whole tibia extracts revealed increased Sirtuin 1 and decreased sclerostin level in SRTAW04 50 mg/kg-treated mice as well as increased mRNA expression of osteocalcin and collagen type 1. SRTAW04 at both doses had no effect on uterine weight.
In vitro, 2-10µM SRTAW04 stimulated osteoblastogenesis and inhibited osteoclastogenesis as indicated by increased alkaline phosphatase activity (+36%), mineralized nodule formation and a dramatic decrease in the generation of multinucleated TRAP+ osteoclasts and resorption pits. These effects were mediated via AMPK activation.
Conclusion: SRTAW04 restores ovariectomy – induced bone loss and structural deterioration in mice. Sirtuin 1 activators hold promise to treat osteoporosis and other age-related pathologies in a concerted manner.
Nothing to Disclose: EC, HA, AB, YG, IG, NK, RS, RD
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