Osteopetrosis is a heterogeneous group of diseases characterized by a generalized excess accumulation of bone and a variety of immune defects. The incisors absent (ia) rat mutation demonstrates these skeletal defects due to reduced bone resorption. These animals also have immune deficiencies involving their natural killer (NK) cell functions and the inflammation-primed activation of their phagocytes. Macrophages and osteoclasts from ia animals have reduced capacity to generate superoxides. Mutant ia rats demonstrate defects in the cascade involved in the conversion of vitamin D binding protein (DBP) to a potent macrophage activating factor (DBP-MAF). Recently, we demonstrated that a number of factors which regulate immune function, e.g. interleukin-2, 1,25(OH)2D3 and DBP-MAF had beneficial effects on both the skeletal and immune functions in the ia mutation. The proposed studies will: 1. Identify the cells in the bone microenvironment which bind DBP-MAF, 2. define the ability of DBP-MAF to stimulate bone resorption in an in vitro system and characterize its direct and/or indirect effects on bone resorption, 3. examine various forms of activated DBP for bone resorbing activity to determine the structural requirements of the activated protein, 4. determine the most effective dose of DBP-MAF for the treatment of osteopetrosis in the ia mutation, 5. evaluate the combined treatment of colony stimulating factor-1 (CSF-1) and DBP-MAF in the ia mutation and 6. evaluate the long-term effects of the various treatment protocols in the ia mutation. Characterization of the etiology of some forms of osteopetrosis and evaluation of potential means of therapeutic intervention are direct applications of the proposed studies. These treatment protocols could be considered for clinical trials. These studies should yield information regarding the mechanism by which DBP-MAF exerts its effects on osteoclastic bone resorption in general. Furthermore, DBP-MAF, because of its association with inflammation, is an important factor involved in inflammation-mediated bone resorption in diseases such as periodontal disease, osteoarthritis and rheumatoid arthritis. An understanding of the disruption of DBP-MAF in osteopetrosis will aid in the development of means to block its activity in these osteolytic diseases.
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