Defective Osteogenic Differentiation in the Development of Osteosarcoma
Figure 1
(a) Mesenchymal stem cells (MSCs) progress down the osteogenic differentiation cascade. MSCs are pluripotent bone marrow stromal cells that are able to differentiate into bone, muscle, tendon, and adipose tissue. Osteogenic differentiation of MSCs is a tightly regulated process by different signaling. Bone morphogenetic proteins (BMPs) and their downstream mediators, such as inhibitor of DNA binding (Id) proteins and connective tissue growth factor (CTGF), are early markers in the osteogenic differentiation cascade. Runx2 and Wnt proteins are important regulators of osteoblastic differentiation. Alkaline phosphatase and Osterix are early/middle markers, while osteocalcin and osteopontin are late markers of bone formation. (b) Defects in osteogenic differentiation lead to osteosarcoma (OS) development. If alterations in the MSC differentiation cascade block the progression to terminally differentiated osteoblasts or osteocytes, it is likely that tumorigenic precursors are formed. Such undifferentiated OS precursors would maintain the ability to proliferate and increase the risk for OS development. Although not well understood, some of the potential defects may include genetic and/or epigenetic changes in Wnt signaling, Rb, p53, and p27. These defects may lead to uncontrolled cell proliferation and disrupted differentiation. Thus, these alterations disrupt the delicate balance between proliferation and differentiation, leading to a tumorigenic phenotype.
