OR24-6 The Sirtuin 1 Activator SRTAW04 Restores Bone Mass and Structure in Ovariectomized Mice A Potential Novel Therapy for Osteoporosis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR24-New Mechanisms in Bone Biology: From Cells to Genetics, & Mice to Men
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:30 PM
Room 121 (Moscone Center)
Einav Cohen-Kfir1, Hanna Artsi2, Alon Bajayo3, Yankel Gabet4, Irina Gurt5, Noga Kalish6, Ron Shahar7 and Rivka Dresner-Pollak*8
1Hadassah Hebrew University Medical Center, Jerusalem, Israel, 2Hebrew University Faculty of Medicine, Jerusalem, Israel, 3Hebrew University, Jerusalem, Israel, 4Tel-Aviv University Faculty of Medicine, Tel-Aviv, Israel, 5Hadassah Hebrew University Faculty of Medicine, Jerusalem, Israel, 6Hebrew University, School of Veterinary Medicine, Rehovot, Israel, 7Hebrew University Koret School of Veterinary Medicine, Rehovot, Israel, 8Hadassah Hebrew Univ Med Ctr, Jerusalem, Israel
Bone loss is an inevitable consequence of aging. Sirtuin 1 (Sirt1) was shown to play a key role in aging and in age-associated conditions such as diabetes and Alzheimer’s disease. We were the first to report that Sirt1 is a player in osteoporosis by showing that it is a major regulator of bone mass in mice, and a repressor of sost gene expression by deacetylating histone 3 at its promoter (1). Synthetic sirtuin 1 activating compounds (STACs) were generated, but were never studied for the treatment of osteoporosis, while their mechanism of action is still controversial.

            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.

(1) Cohen-Kfir E et al., Endocrinology 2011 152(12):4514-24.

Nothing to Disclose: EC, HA, AB, YG, IG, NK, RS, RD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

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