The role of HGF and other multiple myeloma cell products in osteoblastogensis from bone marrow stem cells.

Multiple myeloma, which is the second most frequent haematological cancer, is du to malignant transformation of antibody producing plasma cells. The tumour cells are found in the bone marrow, and severe bone degradation is characteristic for the disease. The presence of the malignant plasma cell within the bone marrow therefore affects the balance between bone forming osteoblasts and bone degrading osteoclasts towards increased bone resorbtion. Thus, both increased activity of osteoclasts, and decreased n umbers and activity of mature osteoblasts have been reported in multiple myeloma. It is now also known that the maturation and activity of osteoclasts is regulated by osteoblasts through for instance expression of RANKL/OPG (Receptor activator of NF-kapp aB Ligand/osteoprotegerin). We have preliminary evidence that the myeloma cell product Hepatocyte Growth Factor (HGF) inhibits in vitro BMP-induced osteoblastogenesis from bone marrow stromal cells. In this project we will explore if myeloma cell products such as HGF have a similar role in an animal model of multiple myeloma, and if inhibition of HGF-signalling by a small-molecular weight tyrosine kinase inhibitor may reverse bone degradation in this model. Furthermore, we will clarify the molecular mech anisms behind the opposing effects of HGF and BMPs on osteoblastogenesis, and in particular how these cytokines affect the expression of downstream effector molecules in osteoblastogenesis such as members of the Wnt-family of ligand and receptors as well as bone specific transcription factors such as Runx2 and Ostrix in the osteoblast lineage. We will also study how HGF and BMP signalling affects osteoclast maturation by their effects on osteoblast differentiation.