期刊
AGING CELL
卷 16, 期 2, 页码 360-376出版社
WILEY
DOI: 10.1111/acel.12566
关键词
aging; BMP signaling; osteoblast; osteoporosis
资金
- Ministry of Science and Technology of China [2013ZX09301307]
- Hong Kong General Research Fund [HKBU479111, HKBU478312, HKBU262913, HKBU261113, CUHK 14108816, CUHK14112915, CUHK489213]
- Natural Science Foundation Council of China [81272045, 81401833, 81470072]
- Research Grants Council & Natural Science Foundation Council of China [N_HKBU435/12]
- Croucher Foundation (Gnt) [CAS14BU/CAS14201]
- Interdisciplinary Research Matching Scheme (IRMS) of Hong Kong Baptist University [RCIRMS/12-13/02, RC-IRMS/13-14/02]
- Hong Kong Baptist University Strategic Development Fund (SDF) [SDF13-1209-P01]
- Hong Kong Research Grants Council (RGC) Early Career Scheme (ECS) [489213]
- Inter-institutional Collaborative Research Scheme of Hong Kong Baptist University [RC-ICRS/14-15/01]
- Faculty Research Grant of Hong Kong Baptist University [FRG1/13-14/024, FRG2/12-13/027, FRG2/14-15/010]
- China Academy of Chinese Medical Sciences [Z0252, Z0293]
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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