On the other hand, it was also reported that reconstituted mice with modified bone marrow in which the expression of miR-125b was enforced exhibited clear myeloproliferative disorders, increasingly progressing to myeloid leukemia [76]. a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression. is altered in about 50% of patients [4,5]. This cancer is most often localized on the metaphysis of the long bones of the extremities, namely, the distal femur, the proximal tibia, and the proximal humerus [6]. Despite recent progress in the therapeutic management of osteosarcomas, the survival rates have not increased in two decades. Thus, to improve the outcome of this pathology, a better understanding of the mechanisms governing the osteoblastic differentiation, the bone-remodeling processes, and, more generally, the carcinogenesis of this cancer are still needed. Worthy of note is that it is now well-established that epigenetic mechanisms such as those SDC1 implicating the small regulatory microRNAs (miRNAs) are of paramount importance to the control of such processes and to the consequent initiation and malignant progression of osteosarcomas. Since the discovery of the first miRNA, implicated in the development of the microscopic worm [7], it has been well-established that these evolutionarily conserved molecules add a novel complex epigenetic regulation layer to the control of gene expression. MiRNAs are small non-coding RNAs of about 22C24 nucleotides in length that disrupt gene expression of messenger RNAs (mRNAs) T-26c through the base-pairing in their 3-untranslated regions T-26c (UTR). Depending on their target sequence homology, they induce either translational repression or mRNA degradation and, consequently, lower the levels of target proteins. Bioinformatics analysis reveals that more than 30% of human genes could be regulated by miRNAs [8]. Because a unique miRNA is sometimes able to target more than a hundred of different mRNAs [9], such regulators can powerfully balance complex networks and constitute critical control nodes in response to the cell environment. In recent years, intensive research has highlighted their implication in various biological processes such as proliferation, cell cycle control, differentiation, or apoptosis. Additionally, they were found to be aberrantly deregulated in a number of diseases, including cancers. Evidence of a relevant implication of miRNAs in cancers was reported for the first time in 2002, after the observation that the miR-15a and -16-1 were often down-regulated or deleted in chronic lymphocytic leukemia cancers [10]. It is worth noting that some miRNAs down-regulate genes with oncogene properties and have, in this case, a tumor suppressor role. On the other hand, some others directly target tumor-suppressor genes and are called oncomiRs. To effectively mediate their inhibitory role, several maturation steps of these molecules are needed. The RNA polymerase II (RNA pol II) is the first player in miRNA biogenesis, allowing for the transcription of a hairpin-structured primary-transcript (pri-miRNA). The latter is then cleaved by the endonuclease III complex DROSHA/DGCR8, leading to a 70-nucleotide length pre-miRNA. The generated pre-miRNA is then exported out of the nucleus by the Exportin-5 before undergoing a second maturation step assumed T-26c by the endoribonuclease DICER, producing the mature miRNA. The latter is finally carried by the AGONAUTE slicer-complex to form an active inhibitor-featured structure termed the miRNA-induced silencing complex (RISC). Considering the fact that the miRNAs promoters bear a close resemblance to those of the protein-coding genes, the expression of these small regulators is modulated by the same regulating processes and, thus, is under the control of a plethora T-26c of transcription factors such as p53. The gene, encoding the p53 protein, is certainly the most famous tumor-suppressor gene in the field of cancer biology due mainly to its genome-safeguard properties. The p53 family is composed of three sequence-specific transcription factors, p53 itself, p63, and p73, regulating the expression of a variety of direct target genes implicated in DNA repair, the induction of cell-cycle arrest, cell senescence, and apoptosis [11,12]. The tumor-suppressor functions of p53 are, moreover, supported by the fact that over 50% of human cancers display mutation or inactivation in this gene [13,14]. In addition, such mutations.