Osteoclasts are the cells responsible for bone loss during osteoporosis and cause debilitating pain and fractures following metastasis to bone of many types of cancer including breast and myeloma. We are examining the roles of Transforming growth factor beta (TGF-?) in osteoclast differentiation and survival as controlling these could provide important new therapies to lessen these health problems. We are also examining the roles of TGF-? in estrogen's protective effects on bone in order to better understand postmenopausal osteoporosis for better therapy to block the bone loss associated with osteoporosis. TGF-?-Inducible Early Gene (TIEG) is rapid response gene that is regulated by members of the TGF-? family. We have discovered that osteoclast precursors that lack TIEG are defective in their ability to differentiate into osteoclasts and osteoblastic cells lacking TIEG are less able to support osteoclast differentiation. We are currently seeking to determine the molecular bases of these defects. These projects are an integral component of Mayo Clinic Bone Group. We are also examining the mechanisms by which the small molecule therapy 2 methoxyestradiol targets osteoclast differentiation and survival to slow osteolytic breast cancer tumor progression. This project is a component of the Mayo Clinic Cancer Center.