Macrophage-stimulating protein / Ron is a novel mediator of osteoclast activation promoting breast cancer-induced bone destruction andOsteoporosis

The purpose of this dissertation is to define how the macrophage- stimulating protein (MSP) / Ron receptor tyrosine kinase pathway is involved in breast cancer-induced bone destruction and osteoclast activation. These studies employed in vitro osteoclast cultures and in vivo animal tumor models as systems to explore the ability of MSP to stimulate osteoclast activity and the ability of MSP-expressing tumor cells to cause bone destruction. I have also explored signaling downstream of Ron in osteoclasts and the requirement for Ron in bone destruction. I have utilized both genetic and pharmacological methods to target this pathway, thereby rigorously testing the ability of this pathway to activate osteoclasts. Included in the first part of this dissertation are two reviews. The first describes the MSP/Ron pathway, its function in cancer and inflammation, and the potential for targeting this pathway pharmacologically. The second review describes various mouse models used to study bone metastasis and bone destruction in vivo. The second part of this dissertation is focused on the ability of MSP/Ron to regulate osteoclast activation. Tumors overexpressing MSP spontaneously metastasize to bone and are osteolytic in an animal model of breast cancer. Here, I explore the function of MSP/Ron in aiding cancer cells to manipulate the iv bone microenvironment, allowing for tumor growth and bone destruction. This study reveals the MSP/Ron pathway as a novel mediator of osteoclast activity, independent of previously established pathways such as RANKL and TGFβ. Additionally, I have demonstrated that the loss or inhibition of the MSP/Ron pathway can protect from bone loss due to both breast cancer and osteoporosis. This evidence establishes the importance of this pathway in osteoclast regulation and the potential for use of Ron inhibitors in preventing bone loss.