The Sirtuin1 Activator SRT3025 Down-Regulates Sclerostin and Rescues Ovariectomy-Induced Bone Loss and Biomechanical Deterioration in Female Mice
The Sirtuin1 Activator SRT3025 Down-Regulates Sclerostin and Rescues Ovariectomy-Induced Bone Loss and Biomechanical Deterioration in Female Mice
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DOI：
10.1210/en.2014-1334
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发表时间：
2014-09-01
期刊：
影响因子：
4.8
通讯作者：
Dresner-Pollak, Rivka
中科院分区：
文献类型：
--
作者：
Artsi, Hanna;Cohen-Kfir, Einav;Dresner-Pollak, Rivka
雌激素缺乏会导致快速的骨质流失和骨骼脆弱。由sost基因编码的硬化蛋白是骨细胞的产物，是骨形成的负调节因子。阻断硬化蛋白可以增加动物和人类的骨量和强度。Sirtuin 1（Sirt 1）是衰老和代谢的参与者，通过在其启动子处脱乙酰化组蛋白3来调节骨量并抑制sost表达。我们询问Sirt 1激活化合物是否可以挽救9周龄C57 BL/6小鼠卵巢切除术（OVX）诱导的骨丢失和生物力学恶化。OVX导致骨骼Sirt 1表达的大幅下降，伴随着sclerostin的增加。从OVX后6周开始，连续6周经口给予SRT 3025（一种Sirt 1激活剂）50和100 mg/kg.d，可完全逆转OVX对椎骨骨量、微结构和股骨生物力学特性的有害影响。用SRT 3025处理降低了骨硬化蛋白表达，增加了皮质骨膜矿化表面和I型前胶原的血清前肽（骨形成标志物）。在体外，在小鼠长骨骨细胞-Y 4骨细胞样细胞系SRT 3025中，sclerostin和失活的β-连环蛋白下调，而Sirt 1抑制剂EX-527则观察到了相反的作用。通过Sirt 1激活化合物激活Sirt 1是下调sclerostin和设计骨质疏松症合成代谢疗法同时改善其他代谢和年龄相关疾病的潜在新途径。
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 beta-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.