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Aging (Albany NY). 2015 Mar;7(3):205-18.

The p53/miR-17/Smurf1 pathway mediates skeletal deformities in an age-related model via inhibiting the function of mesenchymal stem cells.

Author information

1
State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China.
2
Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China.
3
Department of Orthodontics, Medical Faculty, University of Bonn, Bonn, Germany.
4
State Key Laboratory of Military Stomatology, Department of Orthodontic, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China.

Abstract

Osteoporosis is an age-related progressive bone disease. Trp53 (p53) is not only a famous senescence marker but also a transcription regulator which played a critical role in osteogenesis. However, how p53 contributes to the bone mass loss in age-related osteoporosis is still unclear. Here, we found that bone mass and osteogenic differentiation capacity of mesenchymal stem cells (MSCs) is significantly reduced with advancing age. Serum levels of TNF-α and INF-γ and senescence-associated β-galactosidase, p16, p21 and p53 are significantly increased in elder mice, but antipodally, osteogenic marker expression of Runx2, ALP and osterix are reduced. Overexpression p53 by lentivirus inhibits osteogenesis in young MSCs in culture and upon implantation in NOD/SCID mice through inhibiting the transcription of miR-17-92 cluster, which is decreased in old mice. In addition, miR-17 mimics could partially rescue the osteogenesis of old MSCs both in vitro an in vivo. More importantly, Smurf1 as a direct target gene of miR-17, plays an important role in the p53/miR-17 cascade acting on osteogenesis. Our findings reveal that p53 inhibits osteogenesis via affecting the function of MSCs through miRNA signaling pathways and provide a new potential target for treatment in future.

KEYWORDS:

aging; mesenchymal stem cells; miR-17; osteogenesis; p53

PMID:
25855145
PMCID:
PMC4394731
DOI:
10.18632/aging.100728
[Indexed for MEDLINE]
Free PMC Article

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