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.
Highlights
Age-related diseases include cancer, cardiovascular disease, diabetes, various neurodegenerative diseases [1], and especially osteoporosis
The osteogenic differentiation capacity of BMMSCs derived from old mice was significantly reduced compared to the ones obtained from young mice, which was evident from the www.impactaging.com results of the alizarin red staining as much as the gene and protein expression analyses of osteogenic marker expression, namely Runx2, ALP and osterix (Fig. 2EG)
Our analyses revealed that in vivo bone formation in terms of volumetric bone mineral density and trabecular bone volume fraction in femur tissue sections and in vitro correspondingly osteogenic differentiation of murine BMMSCs are reduced with advancing age
Summary
Age-related diseases include cancer, cardiovascular disease, diabetes, various neurodegenerative diseases [1], and especially osteoporosis. (BMMSCs) are pluripotent cells with the potential for self-renewal and multiple differentiations into other cell types, dedicating them for regenerative medicine and tissue engineering, as they provide tissue maintenance and repair after damaging insults [2, 3]. Bone homeostasis is supposed to fundamentally depend on the transformation potential of BMMSCs, in this case different into osteoblastic cells [4]. The qualification of BMMSCs for recovery of multiple tissue systems is contingently compromised with age [3, 5]. As senescent cells can remain and agglomerate in tissues in contrast to apoptotic cells that are immediately removed by hostdefensively processes, their existence can profoundly affect homeostatic mechanisms of the whole body [6,7,8]
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