Ji Yaoting, Ke Yongxin, Gao Song
Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School & Hospital of Stomatology, Wuhan UniversityWuhan 430079, Hubei, China.
Am J Transl Res. 2017 Jun 15;9(6):2933-2944. eCollection 2017.
Stimulatory and inhibitory effects of Notch signaling pathway on osteogenesis were both widely reported, questioning the effectiveness of small molecules targeting the Notch pathway for prevention or treatment of bone loss diseases. Here we showed that Notch signaling is activated in osteocytes embedded within the mineralized matrix and in late stages of bone marrow mesenchymal cell osteogenic cultures. Inhibition of Notch signaling markedly reduced mineralization activities of bone marrow mesenchymal cells and inhibited expressions of mineralization-associated genes when Notch ligand Jagged1 was conditionally deleted, confirming the essential roles of Notch signaling in mineralization stages of osteoblast differentiation. Moreover, intermittent activation of Notch signaling showed significant increases of bone formation in mice, rats and ovariectomized rats. A two-phase action model of Notch signaling in osteogenesis is proposed, where activation of Notch signaling in early stages of osteoblast differentiation results in proliferation of immature preosteoblast lineage cells and activation in late stages promotes differentiation of osteoblasts into osteocytes. Moreover, valproic acid is a strong activator of Notch signaling, and yearly administration of valproic acid daily showed little side effects, indicating that long term and intermittent activation of Notch signaling will be a safe and ideal way to promote anabolic bone formation for treatment of osteoporosis. Therefore, Notch signaling pathway is a good therapeutic target for bone loss diseases, and valproic acid, resveratrol and other Notch activators are promising therapeutic molecules for promoting anabolic bone formation when administered intermittently.
Notch信号通路对成骨的刺激和抑制作用均有广泛报道，这使得针对Notch通路的小分子药物预防或治疗骨质流失疾病的有效性受到质疑。在此我们表明，在矿化基质中的骨细胞以及骨髓间充质细胞成骨培养的后期阶段，Notch信号被激活。当Notch配体Jagged1被条件性缺失时，Notch信号的抑制显著降低了骨髓间充质细胞的矿化活性，并抑制了矿化相关基因的表达，证实了Notch信号在成骨细胞分化矿化阶段的重要作用。此外，间歇性激活Notch信号在小鼠、大鼠和去卵巢大鼠中均显示出骨形成显著增加。我们提出了Notch信号在成骨过程中的两阶段作用模型，即成骨细胞分化早期Notch信号的激活导致未成熟前成骨细胞系细胞增殖，后期激活促进成骨细胞向骨细胞分化。此外，丙戊酸是Notch信号的强效激活剂，每日给予丙戊酸一年显示出几乎没有副作用，这表明长期间歇性激活Notch信号将是促进合成代谢性骨形成以治疗骨质疏松症的安全理想方法。因此，Notch信号通路是骨质流失疾病的良好治疗靶点，丙戊酸、白藜芦醇和其他Notch激活剂在间歇性给药时是促进合成代谢性骨形成的有前景的治疗分子。
