The Sirtuin1 Activator SRT3025 Down-Regulates Sclerostin and Rescues Ovariectomy-Induced Bone Loss and Biomechanical Deterioration in Female Mice

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. We asked 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/kg·d 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 murine long bone osteocyte-Y4 osteocyte-like cell line SRT3025 down-regulated sclerostin and inactive β-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.

SIRT1 is a positive regulator of the master osteoblast transcription factor, RUNX2

“…Preliminary evidence gives reason to be optimistic: SIRT1 appears to promote commitment of MSCs towards the osteoblast lineage [45–46, 48–49] and repress differentiation of osteoclasts [43, 50–51]. Indeed, recent studies with second and third generation SIRT1 agonists have shown even greater promise in preserving bone mass in mice [14, 52], raising hopes for a possible novel therapeutic for osteoporosis in the not so distant future.…”

Hormonal and systemic regulation of sclerostin

“…Thus, Artsi et al [44] found that ovariectomy in mice resulted in a marked decrease in skeletal Sirt1 expression accompanied by an increase in sclerostin. Interestingly, oral administration of SRT3025, a Sirt1 activator, reversed the deleterious skeletal effects of ovariectomy and also reduced bone sclerostin expression.…”

Effects of dietary resveratrol on excess-iron-induced bone loss via antioxidative character

“…The major impacts are antioxidative, antiinflammatory, cardioprotective, antiaging as well as anticancer and chemopreventive [13]. Sirtuin1 (Sirt1), an NAD + -dependent deacetylase and a key player in aging and metabolism, has been shown to regulate bone mass [14]. As a natural Sirt1 agonist, RES can upregulate the level of FOXOs and increase the activities of antioxidant enzymes in C2C12 mouse myoblasts cells and human monocytic THP-1 cells under oxidative stress conditions [15,16].…”