Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging.
Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging.
复制标题
成骨细胞内增加的 PLEKHO1 抑制 Smad 依赖性 BMP 信号传导，从而抑制衰老过程中的骨形成
DOI：
10.1111/acel.12566
复制
发表时间：
2017-04
期刊：
影响因子：
7.8
通讯作者：
Zhang G
中科院分区：
文献类型：
--
作者：
Liu J;Liang C;Guo B;Wu X;Li D;Zhang Z;Zheng K;Dang L;He X;Lu C;Peng S;Pan X;Zhang BT;Lu A;Zhang G
新出现的证据表明，蛋白质泛素化的失调在衰老相关疾病中起着至关重要的作用。Smad依赖的经典BMP信号通路是成骨细胞骨形成不可或缺的，其可被BMP信号转导的关键分子Smad 1/5的泛素化和随后的蛋白酶体降解破坏。然而，Smad 1/5泛素化的失调和BMP信号通路的破坏是否是年龄相关性骨形成减少的原因仍有待研究。Pleckstrin homology domain-containing family O member 1（PLEKHO 1）是一种以前发现的泛素化相关分子，可以特异性靶向Smurf 1的WW结构域之间的连接区，以促进Smad 1/5的泛素化。在这里，我们发现骨折患者或老年啮齿动物骨标本中PLEKHO 1表达的年龄相关性增加，这与Smad依赖性BMP信号传导和骨形成的年龄相关性减少有关。通过遗传学方法，我们证明成骨细胞中Plekho 1的缺失可以促进Smad依赖的BMP信号传导，并减轻年龄相关的骨形成减少。此外，成骨细胞特异性Smad 1过表达对衰老过程中的骨形成有有益的影响，这可以在成骨细胞内过表达Plekho 1后被抵消。通过药理学方法，我们发现成骨细胞靶向的Plekho 1 siRNA治疗可以增强Smad依赖的BMP信号传导并促进衰老啮齿动物的骨形成。总之，这表明增加的PLEKHO 1可以抑制Smad依赖性BMP信号传导以抑制衰老期间的骨形成，表明靶向成骨细胞中的PLEKHO 1作为逆转衰老期间已建立的骨质疏松症的新型骨合成代谢策略的翻译潜力。
Emerging evidence indicates that the dysregulation of protein ubiquitination plays a crucial role in aging‐associated diseases. Smad‐dependent canonical BMP signaling pathway is indispensable for osteoblastic bone formation, which could be disrupted by the ubiquitination and subsequent proteasomal degradation of Smad1/5, the key molecules for BMP signaling transduction. However, whether the dysregulation of Smad1/5 ubiquitination and disrupted BMP signaling pathway is responsible for the age‐related bone formation reduction is still underexplored. Pleckstrin homology domain‐containing family O member 1 (PLEKHO1) is a previously identified ubiquitination‐related molecule that could specifically target the linker region between the WW domains of Smurf1 to promote the ubiquitination of Smad1/5. Here, we found an age‐related increase in the expression of PLEKHO1 in bone specimens from either fractured patients or aging rodents, which was associated with the age‐related reduction in Smad‐dependent BMP signaling and bone formation. By genetic approach, we demonstrated that loss of Plekho1 in osteoblasts could promote the Smad‐dependent BMP signaling and alleviated the age‐related bone formation reduction. In addition, osteoblast‐specific Smad1 overexpression had beneficial effect on bone formation during aging, which could be counteracted after overexpressing Plekho1 within osteoblasts. By pharmacological approach, we showed that osteoblast‐targeted Plekho1 siRNA treatment could enhance Smad‐dependent BMP signaling and promote bone formation in aging rodents. Taken together, it suggests that the increased PLEKHO1 could suppress Smad‐dependent BMP signaling to inhibit bone formation during aging, indicating the translational potential of targeting PLEKHO1 in osteoblast as a novel bone anabolic strategy for reversing established osteoporosis during aging.