Bone Abstracts

Osteosarcoma is the most prevalent primary bone tumor that occurs mainly during adolescence. Osteosarcoma is an aggressive mesenchymal tumor that often arises due to mutations in the tumor suppressor gene p53. Treatment of osteosarcoma patients includes chemotherapy, radiation therapy and surgical approaches. Nevertheless, at advanced stages the survival rate is rather low. Thus, a better understanding of the underlying biology of osteosarcoma might help to develop novel therapeutic approaches to improve the current treatment options. Runx2 is a transcription factor that promotes differentiation and restricts proliferation of osteoblasts under physiological conditions. In osteosarcoma, expression of Runx2 is often increased and its function is deregulated. We defined pathological roles of Runx2 in the etiology of osteosarcoma and mechanisms by which Runx2 expression is increased. Runx2 is often highly expressed in human osteosarcoma biopsies and cell lines. Small interference RNA (siRNA)-mediated depletion of Runx2 inhibits growth of U2OS osteosarcoma cells. Runx2 levels are inversely linked to loss of p53, which predisposes to osteosarcoma, in distinct osteosarcoma cell lines and osteoblasts. Runx2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated Runx2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated Runx2 targeting microRNAs (miRNAs) in human osteosarcoma cells compared to mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated Runx2 targeting miRNA in osteosarcoma. Exogenous supplementation of miR-34c markedly decreases Runx2 protein levels, while 3’UTR reporter assays establishes Runx2 as a direct target of miR-34c in osteosarcoma cells. Importantly, Nutlin-3 mediated stabilization of p53 increases the expression of miR-34c and decreases the abundance of Runx2. Thus, a novel Runx2-p53-miR34 network controls cell growth of osseous cells and is compromised in osteosarcoma. This regulatory network could provide the opportunity for novel therapeutic interventions, i.e. the exogenous reconstitution of osteosarcoma with miR-34c. MicroRNAs are already in the development as potential drugs and could also be useful for future cancer therapies.

Disclosure: Received consultation and speaker fee from Lilly and Amgen.