p53 Loss Increases the Osteogenic Differentiation of Bone Marrow Stromal Cells

Abstract

The tumor suppressor, p53, plays a critical role in suppressing osteosarcoma. Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) have been suggested to give rise to osteosarcomas. However, the role of p53 in BMSCs has not been extensively explored. Here, we report that p53 regulates the lineage choice of mouse BMSCs (mBMSCs). Compared to mBMSCs with wild type p53, mBMSCs deficient in p53 have enhanced osteogenic differentiation, but with similar adipogenic and chondrogenic differentiation. The role of p53 in inhibiting osteogenic lineage differentiation is mainly through the action of Runx2, a master transcription factor required for the osteogenic differentiation of mBMSCs. We find that p53 indirectly represses the expression of Runx2 by activating the microRNA-34 family, which suppresses the translation of Runx2. Since osteosarcoma may derive from BMSCs, we examined whether p53 has a role in the osteogenic differentiation of osteosarcoma cells and found that osteosarcoma cells with p53 deletion have higher levels of Runx2 and faster osteogenic differentiation than those with wild type p53. A systems biology approach reveals that p53-deficient mBMSCs are more closely related to human osteosarcoma while mBMSCs with wild type p53 are similar to normal human BMSCs. In summary, our results indicate that p53 activity can influence cell fate specification of mBMSCs, and provide molecular and cellular insights into the observation that p53 loss is associated with increased osteosarcoma incidence.

cFOS-SOX9 Axis Reprograms Bone Marrow-Derived Mesenchymal Stem Cells into Chondroblastic Osteosarcoma

“…Pathological analyses revealed that 100% of generated tumors were osteoblastic OS containing woven bones and osteoid (Figure 1). This finding is consistent with our previous in vitro observation showing that p53_KO BMSCs are predisposed to osteoblastic differentiation (He et al., 2015). Thus, the default subtype of OS formed from p53_KO BMSCs is osteoblastic OS.

Figure 1p53_KO BMSCs Generate Osteoblastic OS(A) H&E staining of two representative tumors formed from p53_KO BMSCs transplanted into NSG mice.

…”

“…The dual roles of cFOS in OS are reminiscent of the dual roles of p53 in BMSCs, in which p53 not only prevents tumorigenesis but also affects the lineage choice of these cells (He et al., 2015). What, then, is the relationship between the roles of cFOS in development and cancer?…”

“…Because of the intrinsic heterogeneous expression of the Cre transgene, the “true” cell of origin of OS is still elusive. Using previously characterized BMSCs isolated from the bone marrow from adult mice (He et al., 2015), our results demonstrate that adult BMSCs indeed have the ability of developing into OS in the transplantation assay. Of note, our results do not exclude the possibility that other cell types, such as osteoblasts, can also serve as cells of origin of OS.…”

“…For ChIP-seq, we followed our previous procedures without major modifications (He et al., 2015, Li et al., 2012, Shin et al., 2016). Pathway analyses using DAVID Bioinformatics Resources were previously described (Huang da et al., 2009, Lee et al., 2010).…”

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

“…It is not simply the loss of WT p53 that drives cells to cancer. The majority of the p53 mutations found in tumors are missense mutations, resulting in production of full-length protein with only one amino acid change [44, 63]. Many of these mutant p53 exhibit a dominant-negative effect over WT p53, mostly by forming mixed tetramers with diminished DNA binding and transactivation activity [64].…”