Artsi Hanna, Cohen-Kfir Einav, Gurt Irina, Shahar Ron, Bajayo Alon, Kalish Noga, Bellido Teresita M, Gabet Yankel, Dresner-Pollak Rivka
Endocrinology and Metabolism Service (H.A., E.C.-K., I.G., R.D.-P.), Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Laboratory of Bone Biomechanics (R.S., N.K.), Koret School of Veterinary Medicine, The Hebrew University of Jerusalem, Rehovot, 76100 Israel; Bone Laboratory (A.B.), The Hebrew University of Jerusalem, Jerusalem, 91120 Israel; Department of Anatomy and Cell Biology (T.M.B.), Division of Endocrinology, Indiana University School of Medicine, Indianapolis, Indiana 46202; and Department of Anatomy and Anthropology (Y.G.), Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978 Israel.
Endocrinology. 2014 Sep;155(9):3508-15. doi: 10.1210/en.2014-1334. Epub 2014 Jun 20.
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.
雌激素缺乏会导致骨量快速流失和骨骼脆弱。由sost基因编码的骨硬化蛋白是骨细胞的产物，是骨形成的负调节因子。阻断骨硬化蛋白可增加动物和人类的骨量和骨强度。沉默调节蛋白1（Sirt1）参与衰老和代谢过程，它通过使组蛋白3在其启动子处去乙酰化来调节骨量并抑制sost表达。我们研究了一种Sirt1激活化合物是否能挽救9周龄C57BL/6小鼠卵巢切除（OVX）诱导的骨量流失和生物力学恶化。OVX导致骨骼中Sirt1表达大幅下降，同时骨硬化蛋白增加。在OVX 6周后开始，以50和100 mg/kg·d的剂量口服Sirt1激活剂SRT3025，持续6周，完全逆转了OVX对椎骨骨量、微结构和股骨生物力学性能的有害影响。用SRT3025治疗可降低骨硬化蛋白表达，并增加皮质骨膜矿化表面和I型前胶原血清前体肽（一种骨形成标志物）。在体外，在小鼠长骨骨细胞-Y4骨细胞样细胞系中，SRT3025下调骨硬化蛋白和无活性的β-连环蛋白，而Sirt1抑制剂EX-527则产生相反的效果。通过Sirt1激活化合物激活Sirt1是一种潜在的新途径，可下调骨硬化蛋白，并设计用于骨质疏松症的合成代谢疗法，同时改善其他代谢和与年龄相关的状况。
