Mesenchymal stem cells from bone marrow stroma are pluripotent and can be expanded ex vivo whilst retaining their multi-potentiality. They therefore provide a convenient ex vivo model for the study of mesenchymal stem cell differentiation. More specifically, the process of stem cell proliferation coupled to osteoblastic differentiation can be closely monitored, permitting the detailed investigation of osteogenic tissue repair in an experimentally accessible model. This research plan describes an investigation designed to discover and evaluate compounds that reverse the effect of Dkk-1 thereby activating the canonical Wnt signaling pathway. This would therefore increase the rate of osteogenic differentiation by MSCs. This proposal tests the central hypothesis that small molecules may have utility in improving osteogenic tissue repair by MSCs in bone degenerative diseases such as multiple myeloma and osteogenesis imperfecta. These molecules could contribute to the development of a novel family of pharmaceutically active agents for the improvement of the natural healing process in humans. There are 3 Specific Aims: ? 1 To investigate the effect of the canonical Wnt inhibitor dickkopf-1 and glycogen-synthase-kinase-3-beta (GSKSb) inhibitors on osteogenic differentiation by mesenchymal stem cells in vitro. ? 2 To optimize a murine model of multiple myeloma that exhibit osteolytic lesions and to test known GSKSb inhibitors for utility in reducing the formation of osteolytic lesions. ? 3 To test the utility of in enhancing osteogenic tissue repair in a murine model of osteogenesis imperfecta. ? Adult stem cells have the potential to dramatically improve regenerative medicine in the future. This proposal is designed to discover molecules that improve the inherent capacity of adult human stem cells to repair bone tissue. These molecules are clinically relevant for the treatment of diseases such as Osteogenesis Imperfecta (brittle bone disease) and malignant bone disease and critical size bone injuries. ? ? ?
