This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This proposal tests the central hypothesis that expression of the osteoinhibtory protein ligand, Dkk-1,contributes to the formation of bone lesions in osteosarcoma and some metastatic bone diseases by inhibiting the natural process of osteogenic differentiation by mesenchymal stem cells. Pharmalogocal induction of canonical Wnt signaling by inhibition of glycogen synthetase kinase , and inhibition of peroxisome-proliferator activated receptor , accelerates osteogenic differentiation by mesenchymal stem cells. These molecules block the action of Dkk-1 and thus may reverse the damage caused by some malignant diseases of the skeleton. There are 4 specific aims. + A1. 'To further validate the utility of Dkk-1 as a blood/tissue marker for malignant and degenerative bone disease in humans. + A2. 'To investigate ex vivo crosstalk between canonical Wnt signaling and the PPAR gamma mediated signaling pathway in human and rodent mesenchymal stem cells from bone marrow stroma in the presence and absence of Dkk-1. + A3. 'To examine the effects of compounds, proteins, and antibodies that have potential to modulate canonical Wnt and PPAR mediated signaling on the levels of adipose and osteoblast progenitors in rodent blood and bone marrow. + A4. 'To examine the potential osteo-inductive effect of such drugs in murine models of malignant bone disease utilizing established cancer lines and tissue derived from osteosarcoma and multiple myeloma patients.
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