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

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 ß-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.

Bre Enhances Osteoblastic Differentiation by Promoting the Mdm2-Mediated Degradation of p53

“…However, Xiao et al did not report the age of the mice, and, more importantly, the morphological characteristics of the bone were not analyzed using micro-CT or histomorphometric approaches. A reported age-dependent decrease in osteoblastic proliferation and differentiation is highly consistent with the reported age-related increase in p53 expression in mice [27,56], and suggests that older Bre knockout mice would display altered bone homeostasis. Aging significantly reduces the quantity of MSCs in the bone marrow and blocks the osteogenic differentiation potential of MSCs, in a partially p53 signaling-dependent manner [56].…”

“…Similarly, we found that modulating Bre expression affected the expression of the transcription factors Runx2, Osx, and Pparg, suggesting a mechanism through which Bre affects the lineage commitment of stem cells. Furthermore, several studies have demonstrated that mbMSCs from osteoporotic OVX mice or older mice have significantly enhanced adipogenic potential, but greatly reduced osteogenic potential [27,44]. Our data suggest that the downregulation of Bre following OVX could be responsible such alterations to the differentiation potential of MSCs.…”

“…p53 signaling pathways are known to be involved in the lineage commitment of MSCs, with their negative regulation of bone formation being well described both in vivo and in vitro [20][21][22][23][24][25][26][27]. Knocking out Mdm2 in osteoblasts significantly impaired murine bone formation, indicating that Mdm2 modulates p53 during in vivo bone development [22].…”

Declining histone acetyltransferase GCN5 represses BMSC‐mediated angiogenesis during osteoporosis

“…These findings underlined the crucial role of BMSCs in regulation of angiogenesis and will be helpful in understanding the cellular basis of osteoporosis. Accumulating evidence suggests that the function of BMSCs is extensively impaired during aging and estrogen deficiency, leading to the progression of osteoporosis (11)(12)(13)(14)(15)(16). In this study, we found that, along with the decline of osteogenic differentiation capacity, osteoporotic BMSCs secreted less angiogenic factors to induce angiogenesis.…”

“…The decline of BMSC function in maintaining bone homeostasis is a seminal mechanism of bone loss in osteoporosis. Our recent studies have confirmed that decreased BMSC osteogenic differentiation leads to bone formation defects during osteoporosis (11)(12)(13)(14)(15)(16), but whether the decline in angiogenesis is related to BMSC dysfunction remains unknown.…”