Aluminum accumulation causes variable bone pathology depending upon the clinical setting and the duration and amount of exposure. In the uremic state, aluminum has been implicated in the pathogenesis of low turnover osteomalacia and aplastic bone disease. In contrast, recent investigations in my lab illustrate that aluminum administration to dogs with normal renal function induces bone pathologies which differ substantially from those observed in these clinical disease states. Relatively low dose aluminum results in a transient reduction in bone formation and resorption and no effects on mineralization, while higher doses of aluminum result in a marked proliferation of osteoblasts and woven osteoid and a sustained inhibition of osteoclastic function. This stimulation of bone formation contrasts with the inhibitory effects of aluminum in clinical disease states and suggests that unknown factors may modulate the expression of aluminum induced effects. The failure to sustain an inhibitory effect on bone cell function with low dose aluminum also suggests the presence of compensatory mechanisms. These observations suggest that the effects of aluminum are complex and dependent upon extraosseous factors and/or deposition of aluminum in discrete compartments of bone cells or matrix. The purpose of this project is: 1) to determine if specific factors which are known modulators of bone turnover, such as PTH, mediate or modify the histologic expression of aluminum on bone; 2) to investigate the relationship between the ultrastructural localization of aluminum within bone cells and matrix with the temporal appearance of bone abnormalities; and 3) to determine if the variable expression of aluminum on bone is mediated by a direct effect on bone cells utilizing cell culture techniques. These studies will aid in defining the specific conditions which render bone susceptible to the deleterious effects of aluminum. Such information will permit formulation of effective therapeutic intervention for the """"""""aluminum-induced"""""""" bone diseases. Indeed, the therapies derived from these investigations may depend not only on removal of aluminum from bone but normalization of ancillary defects as well.
