Title; Effect of Gallium on Bone The major objective of this continuation application is to study the effects of gallium, a group IIIa meal, on bone metabolism. The studies proposed are a logical extension of our previous work showing gallium to be a safe and highly effective agent for the treatment of hypercalcemia of malignancy. Our hypothesis is that gallium blocks bone resorption and enhances bone formation by favorably altering the function of bone cells (osteoclasts and osteoblasts) as well as physicochemically altering mineral properties. The purpose of the proposed experiments is to demonstrate that all these mechanisms contribute to the beneficial effects of gallium on bone metabolism. Our approach towards this objective will be to apply physical and biochemical methods to a panel of synthetic, cell and organ culture systems as well as in vivo models in order to study isolated aspects of bone metabolism in depth. Specific experiments include the use of a synchrotron generated energy source to localize at the microscopic and atomic levels, the trace of gallium that are present in the bone matrix. In vitro, cell-mediated mineral formation and growth will be measured. Bone collagen synthesis will be studied using bone rudiments, osteoblast cell cultures and a rodent model. Gene-regulation of osteocalcin (bone-Gla protein) will be examined using specific cDNA probes. In vivo, bone mineralization and remodeling will be studied using mineralized and demineralized bone implants. The biomechanical properties of rat bones will be tested to evaluate the strength of bone produced in the presence of gallium. These proposed studies are meant to provide insights into the mechanisms of action of gallium in bone. In addition, they provide a basis for the design and realization of future clinical trials with this therapeutically useful new agent.
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