Department of Clinic of Spine Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 200082, Shanghai, China.
Cell Death Dis. 2021 May 15;12(5):497. doi: 10.1038/s41419-021-03784-8.
Bone health requires adequate bone mass, which is maintained by a critical balance between bone resorption and formation. In our study, we identified beraprost as a pivotal regulator of bone formation and resorption. The administration of beraprost promoted differentiation of mouse bone mesenchymal stem cells (M-BMSCs) through the PI3K-AKT pathway. In co-culture, osteoblasts stimulated with beraprost inhibited osteoclastogenesis in a rankl-dependent manner. Bone mass of p53 knockout mice remained stable, regardless of the administration of beraprost, indicating that p53 plays a vital role in the bone mass regulation by beraprost. Mechanistic in vitro studies showed that p53 binds to the promoter region of neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) to promote its transcription. As a ubiquitinating enzyme, Nedd4 binds to runt-related transcription factor 2 (Runx2), which results in its ubiquitination and subsequent degradation. These data indicate that the p53-Nedd4-Runx2 axis is an effective regulator of bone formation and highlight the potential of beraprost as a therapeutic drug for postmenopausal osteoporosis.
骨骼健康需要足够的骨量，而这是通过骨吸收和形成之间的关键平衡来维持的。在我们的研究中，我们发现贝前列素是骨形成和吸收的关键调节因子。贝前列素的给药通过 PI3K-AKT 途径促进了小鼠骨髓间充质干细胞（M-BMSCs）的分化。在共培养中，贝前列素刺激的成骨细胞以依赖 rankl 的方式抑制破骨细胞生成。无论是否给予贝前列素，p53 敲除小鼠的骨量保持稳定，这表明 p53 在贝前列素调节骨量方面起着至关重要的作用。体外机制研究表明，p53 与神经元前体细胞表达的发育下调 4（Nedd4）的启动子区域结合，促进其转录。作为一种泛素化酶，Nedd4 与 runt 相关转录因子 2（Runx2）结合，导致其泛素化和随后的降解。这些数据表明，p53-Nedd4-Runx2 轴是骨形成的有效调节因子，并突出了贝前列素作为绝经后骨质疏松症治疗药物的潜力。
