School of Chinese Medicine
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.
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Wiley Open Access
© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This study was supported by the Ministry of Science and Technology of China (2013ZX09301307 to A.L.), the Hong Kong General Research Fund (HKBU479111 to G.Z., HKBU478312 to G.Z., HKBU262913 to G.Z., HKBU261113 to A.L., CUHK 14108816 to B.Z., CUHK14112915 to B.Z. and CUHK489213 to B.Z.), the Natural Science Foundation Council of China (81272045 to G.Z. 81272045 to B.G., 81401833 to B.G. and 81470072 to X.H.), the Research Grants Council & Natural Science Foundation Council of China (N_HKBU435/12 to G.Z.), the Croucher Foundation (Gnt#CAS14BU/CAS14201 to G.Z.), the Interdisciplinary Research Matching Scheme (IRMS) of Hong Kong Baptist University (RC-IRMS/12-13/02 to A.L. and RC-IRMS/13-14/02 to G.Z.), the Hong Kong Baptist University Strategic Development Fund (SDF) (SDF13-1209-P01 to A.L.), the Hong Kong Research Grants Council (RGC) Early Career Scheme (ECS) (489213 to G.Z.), the Inter-institutional Collaborative Research Scheme of Hong Kong Baptist University (RC-ICRS/14-15/01 to G.Z.), the Faculty Research Grant of Hong Kong Baptist University (FRG1/13-14/024 to G.Z. FRG2/12-13/027 to G.Z. and FRG2/14-15/010 to G.Z.), and the China Academy of Chinese Medical Sciences (Z0252 and Z0293 to A.L.).
Link to Publisher's Edition
Liu, Jin, Chao Liang, Baosheng Guo, Xiaohao Wu, Defang Li, Zongkang Zhang, Kang Zheng, Lei Dang, Xiaojuan He, Changwei Lu, Songlin Pan, Xiaohua Pan, Bao-Ting Zhang, Aiping Lu, and Ge Zhang. "Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging." Aging Cell 16.2 (2017): 360-376.
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