Abstract:

Estrogen deficiency leads to rapid bone loss and skeletal fragility. Sclerostin, encoded by the sost gene,
and a product of the osteocyte, is a negative regulator of bone formation. Blocking sclerostin increases
bone mass and strength in animals and humans. Sirtuin1 (Sirt1), a player in aging and metabolism,
regulates bone mass and inhibits sost expression by deacetylating histone 3 at its promoter.Weasked
whether a Sirt1-activating compound could rescue ovariectomy (OVX)-induced bone loss and biomechanical
deterioration in 9-week-old C57BL/6 mice. OVX resulted in a substantial decrease in skeletal
Sirt1 expression accompanied by an increase in sclerostin. Oral administration of SRT3025, a Sirt1
activator, at 50 and 100 mg/kgd for 6 weeks starting 6 weeks after OVX fully reversed the deleterious
effects of OVX on vertebral bone mass, microarchitecture, and femoral biomechanical properties.
Treatment with SRT3025 decreased bone sclerostin expression and increased cortical periosteal mineralizing
surface and serum propeptide of type I procollagen, a bone formation marker. In vitro, in the
murinelongboneosteocyte-Y4 osteocyte-like cell lineSRT3025down-regulated sclerostinandinactive
-catenin, whereas a reciprocal effect was observed with EX-527, a Sirt1 inhibitor. Sirt1 activation by
Sirt1-activating compounds is a potential novel pathway to down-regulate sclerostin and design anabolic
therapies for osteoporosis concurrently ameliorating other metabolic and age-associated
conditions. (Endocrinology 155: 3508–3515, 2014)