Raman spectroscopy used in combination with anatomic assessment by microCT, digital Faxitron and histomorphometry are revolutionizing the ways in which bone properties and structure can be assessed. They make it possible to interrogate the material composition at specific sites in bone, and thus give unique information on bone quality and reasons for fragility.. In this application, we wish to apply these technologies (available to us in the School of Engineering at Vanderbilt) to examine the effects of myeloma on bone in a well-established preclinical model of myeloma, and to determine the effects of an effective monoclonal antibody to TGF-beta ligands on these functional properties of bone. There are several reasons for this approach. Myeloma is a disease characterized by catastrophic effects on the skeleton resulting in intractable pain and susceptibility to fracture, indicating a marked increase in bone fragility. It is also relatively common in veterans. We plan to study the role of TGF-beta in the bone disease of myeloma because of two recent observations - firstly, TGF-beta has been shown in genetic mouse models to have unexpected specific effects on bone quality that have been demonstrated by Raman spectroscopy associated with decreased resistance to a compression force (Balooch et al., 2005), and secondly, recent in vitro observations with small molecule inhibitors of TGF-beta signaling have suggested that inhibiting TGF-beta signaling in osteoblasts causes enhanced osteoblast differentiation and reduction in myeloma tumor burden (Matsumoto and Abe, 2006). Our hypothesis is that in myeloma, excess TGF-beta in the bone-myeloma cell microenvironment (a) impairs osteoblast differentiation and bone quality, and this impairment in osteoblast differentiation enhances tumor growth indirectly, and (b) enhances tumor growth directly. This hypothesis will be tested using the approaches indicated below. Our goal is to determine (1) if anti-TGF-beta therapy influences bone quality and reduces tumor burden at the myeloma - bone interface, (2) if the effects of anti-TGF-beta therapy are effective in combination with other therapeutic approaches in myeloma, and (3) if the effects of impaired TGF-beta signaling in myeloma are mediated by myeloma cells, or by host cells by the use of genetic mice with conditional knockout of TGF-beta signaling in specific cells in the bone marrow microenvironment. These preclinical studies should provide a guide for the design of phase II clinical studies in patients with myeloma bone disease to determine the efficacy of anti- TGF-beta approaches.
Narrative (Relevance) Potential Impact on Veterans Health Care: We are focusing on myeloma because it is an important malignancy in the Veteran population. It is most common in males of middle age and beyond, and twice as common in African-Americans. These are two groups over-represented in the Veteran population.