Liu Jin, Liang Chao, Guo Baosheng, Wu Xiaohao, Li Defang, Zhang Zongkang, Zheng Kang, Dang Lei, He Xiaojuan, Lu Changwei, Peng Songlin, Pan Xiaohua, Zhang Bao-Ting, Lu Aiping, Zhang Ge
Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
Aging Cell. 2017 Apr;16(2):360-376. doi: 10.1111/acel.12566. Epub 2017 Jan 13.
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.
新出现的证据表明，蛋白质泛素化失调在衰老相关疾病中起关键作用。Smad依赖的经典BMP信号通路对成骨细胞的骨形成至关重要，而BMP信号转导的关键分子Smad1/5的泛素化及随后的蛋白酶体降解可能会破坏该通路。然而，Smad1/5泛素化失调和BMP信号通路破坏是否导致与年龄相关的骨形成减少仍未得到充分研究。含pleckstrin同源结构域的O家族成员1（PLEKHO1）是先前鉴定的一种泛素化相关分子，它可以特异性靶向Smurf1的WW结构域之间的连接区，以促进Smad1/5的泛素化。在这里，我们发现骨折患者或衰老啮齿动物的骨标本中PLEKHO1的表达随年龄增加，这与Smad依赖的BMP信号和骨形成的年龄相关减少有关。通过遗传学方法，我们证明成骨细胞中Plekho1的缺失可以促进Smad依赖的BMP信号，并减轻与年龄相关的骨形成减少。此外，成骨细胞特异性Smad1过表达对衰老过程中的骨形成有有益作用，而成骨细胞中过表达Plekho1后这种作用会被抵消。通过药理学方法，我们表明成骨细胞靶向的Plekho1 siRNA治疗可以增强Smad依赖的BMP信号，并促进衰老啮齿动物的骨形成。综上所述，这表明衰老过程中PLEKHO1增加可能抑制Smad依赖的BMP信号以抑制骨形成，这表明靶向成骨细胞中的PLEKHO1作为一种新型骨合成代谢策略来逆转衰老过程中已有的骨质疏松症具有转化潜力。
